レビュー論文：フィチン酸の摂取、健康と病気：「汝の食物は汝の薬となり、薬は汝の食物となる」(Phytate Intake, Health and Disease: “Let Thy Food Be Thy Medicine and Medicine Be Thy Food”)

出典：https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9855079/

Antioxidants (Basel). 2023 Jan; 12(1): 146. Published online 2023 Jan 7. doi: 10.3390/antiox12010146
PMCID: PMC9855079
PMID: 36671007

Authors
Antelm Pujol,1,*† Pilar Sanchis,2,† Felix Grases,2 and Luis Masmiquel1,*†

Stanley Omaye, Academic Editor

Copyright © 2023 by the authors.
Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

著作権 © 2023 Authors。
被許諾者 MDPI、Basel、スイス。この記事は、クリエイティブ コモンズ アトリビューション(CC BY)ライセンス (https://creativecommons.org/licenses/by/4.0/) の条件に基づいて配布されるオープン アクセス記事です。

Abstract

Phytate (myo-inositol hexakisphosphate or InsP6) is the main phosphorus reservoir that is present in almost all wholegrains, legumes, and oilseeds. It is a major component of the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets. Phytate is recognized as a nutraceutical and is classified by the Food and Drug Administration (FDA) as Generally Recognized As Safe (GRAS). Phytate has been shown to be effective in treating or preventing certain diseases. Phytate has been shown to inhibit calcium salt crystallization and, therefore, to reduce vascular calcifications, calcium renal calculi and soft tissue calcifications. Moreover, the adsorption of phytate to the crystal faces can inhibit hydroxyapatite dissolution and bone resorption, thereby playing a role in the treatment/prevention of bone mass loss. Phytate has a potent antioxidation and anti-inflammatory action. It is capable of inhibiting lipid peroxidation through iron chelation, reducing iron-related free radical generation. As this has the effect of mitigating neuronal damage and loss, phytate shows promise in the treatment/prevention of neurodegenerative disease. It is reported that phytate improves lipid and carbohydrate metabolism, increases adiponectin, decreases leptin and reduces protein glycation, which is linked with macrovascular and microvascular diabetes complications. In this review, we summarize the benefits of phytate intake as seen in in vitro, animal model, epidemiological and clinical trials, and we also identify questions to answer in the future.

フィチン酸塩(ミオイノシトールヘキサキスリン酸またはInsP6)は、ほぼすべての全粒穀物、豆類、油糧種子に存在する主要なリン貯蔵物質である。それは、地中海式食事法および高血圧症予防のための食事療法(DASH)の主要成分である。フィチン酸塩は栄養補助食品として認識され、アメリカ食品医薬品局(FDA)によって一般的に安全と認められる(GRAS)として分類されている。フィチン酸塩は特定の疾患の治療または予防に有効であることが示されている。フィチン酸塩はカルシウム塩結晶化を阻害し、従って血管石灰化、カルシウム腎結石および軟組織石灰化を減少させることが示されている。さらに、結晶面へのフィチン酸塩の吸着はヒドロキシアパタイト溶解と骨吸収を阻害することができ、それによって骨量減少の治療/予防に役割を果たす。フィチン酸塩は強力な抗酸化および抗炎症作用を有する。それは鉄キレート化を介して脂質過酸化を阻害することができ、鉄関連のフリーラジカル生成を減少させる。これはニューロン損傷と喪失を軽減する効果を有するので、フィチン酸は神経変性疾患の治療/予防に有望である。フィチン酸は脂質および炭水化物代謝を改善し、アディポネクチンを増加させ、レプチンを減少させ、大血管および微小血管糖尿病合併症と関連する蛋白質糖化を低下させることが報告されている。このレビューでは、in vitro、動物モデル、疫学的および臨床試験で見られるフィチン酸塩摂取の利点を要約し、また将来答えるべき疑問を特定する。

Keywords: phytate, InsP6, phytin, Mediterranean diet, DASH diet

1. Introduction

The influence of nutrition is crucial for the prevention and even the cure of several diseases. In fact, healthy eating patterns and regular physical activity could prevent up to 80% of instances of coronary heart disease, 90% of type 2 diabetes (T2DM) cases and 30% of all cancers [1]. The Mediterranean diet is characterized by a high intake of plant food (e.g., fruits, vegetables, breads and cereals), beans, nuts, seeds and olive oil [2]. The traditional Mediterranean diet assumes the consumption of about 1 g of phytate per day, accompanied by an appropriate amount of other minerals and bioactive components [3]. Other diets, such as the European/American diet, can provide up to 2 g of phytate per day [4]. The administration of high doses of phytate must be accompanied by an adequate content of minerals. The Mediterranean and DASH diet provide an adequate amount of legumes, whole cereals and nuts, which are rich in phytate and other minerals, in order to not negatively affect the mineral balance [3,4]. In this way, Serra-Majem et al., 2009 [5], showed that a higher adherence to a Mediterranean diet was associated with a lower inadequate intake of zinc, iodine, vitamin E, magnesium, iron, vitamin B1, vitamin A, selenium, vitamin C and folic acid in comparison with other Western diets such as the American diet.

栄養の影響は、いくつかの病気の予防や治癒にも重要である。実際、健康的な食事パターンと定期的な運動は、冠動脈疾患の症例の最大80%、2型糖尿病(T2DM)の症例の90%、および全てのがんの30%を予防する可能性がある[1]。地中海式食事法の特徴は、植物性食品(例えば、果物、野菜、パン、穀物など)、豆類、ナッツ類、種子類、オリーブ油の摂取量が多いことである[2]。伝統的な地中海式食事法では、1日に約1gのフィチン酸塩を摂取し、他のミネラルや生理活性成分を適量摂取すると仮定している[3]。ヨーロッパ/アメリカの食事法のような、他の食事では、フィチン酸塩を1日2gまで摂取できる[4]。高用量のフィチン酸塩の投与には、十分な量のミネラルが必要である。地中海食およびDASH食事法は、ミネラルバランスに負の影響を与えないために、フィチン酸塩および他のミネラルが豊富な豆類、全粒穀物およびナッツを十分な量提供する[3, 4]。このようにして、Serra-Majem et al., 2009[5]は、地中海式食事の固守が高いほど、亜鉛、ヨウ素、ビタミンE、マグネシウム、鉄、ビタミンB1、ビタミンA、セレン、ビタミンCおよび葉酸の不十分な摂取量が少ないことと関連していることを示した。

Myo-inositol hexakisphosphate (InsP6), also known as phytic acid or phytate, is the main phosphorus reservoir that is present in almost all wholegrains, legumes and oilseeds [4]. In plant foods, it is found as a calcium–magnesium salt, called phytin. When phytate is consumed in large amounts, by itself and without being processed/cooked, it can reduce the absorption of some minerals. This has led to phytate being classified by some authors as an antinutrient. Nevertheless, this effect is only seen in laboratory conditions, and real-world data in humans do not demonstrate mineral deficiencies induced by phytate intake. Phytate is instead considered a nutraceutical: a compound that could treat or prevent disease or disorders through a variety of bioactive (e.g., antioxidant, immunomodulatory, lipid lowering) functions [1]. These properties and multiple health benefits have been repeatedly seen in the scientific literature. The FDA classify phytin as Generally Recognized As Safe (GRAS) [4].

フィチン酸またはフィチン酸塩としても知られるミオイノシトールヘキサキスリン酸(InsP6)は、ほぼすべての全粒穀物、豆類および油糧種子に存在する主要なリン貯蔵物質である[4]。植物性食品には、フィチンと呼ばれるカルシウム-マグネシウム塩として判明されている。フィチン酸塩を加工/調理せずにそれだけで大量に摂取すると、一部のミネラルの吸収を低下させる可能性がある。このため、フィチン酸は一部の著者によって抗栄養素として分類されている。それにもかかわらず、この影響は実験室の条件でのみ見られ、人間における実際のデータはフィチン酸摂取によって誘発されるミネラル欠乏を実証していない。代わりに、フィチン酸塩は栄養補助食品と考えられています：これは、さまざまな生物活性(抗酸化作用、免疫調節作用、脂質低下作用など)機能を介して病気や障害を治療または予防できる化合物です[1]。これらの特性と複数の健康上の利点は、科学文献で繰り返し見られてきた。FDAはフィチンを一般に安全と認められる物質(GRAS)に分類している[4]。

Since the discovery of the molecule phytate, research has shown that it may aid essential physiological functions, as well as offer anti-oxidant, anti-inflammatory, anti-cancer properties, be anti-diabetic, neuroprotective, antimicrobial and moreover, have the ability to prevent bone mass loss and decrease pathological calcification such as vascular calcification and renal lithiasis [4,6,7,8]. It has also demonstrated that the ingestion of phytate also generate other inositol phosphates (InsP5, InsP4, InsP3, InsP2), which can also play an important role in these pathological conditions [8]. Phytate has shown promising results in the treatment and prevention of medical conditions that have no current treatment (or where treatment options are prohibitively expensive) in in vitro data, animal models and in some human clinical trials (Figure 1). Our objective with this review is to summarize more than 50 years of research into the role of phytate in multiple health conditions and to identify questions that will need to be answered in the future.

フィチン酸分子の発見以来、研究は、それが本質的な生理学的機能を助けるだけでなく、抗酸化、抗炎症、抗癌特性を提供し、抗糖尿病、神経保護、抗菌性であり、さらに、骨量損失を防ぎ、血管石灰化や腎結石症のような病理学的石灰化を減少させる能力を有することを示した[4, 6, 7, 8]。また、フィチン酸の摂取によって他のイノシトールリン酸(InsP5、InsP4、InsP3、InsP2)が生成されることも生成され、これらの病的状態にも重要な役割を果たしている可能性があることも実証されています[8]。フィチン酸塩は、in vitroデータ、動物モデル、およびいくつかの人間の臨床試験において、現在の治療法がない(または治療選択肢が法外に高価な)病状の治療および予防において有望な結果を示している(図1)。このレビューの目的は、複数の健康状態におけるフィチン酸塩の役割に関する50年以上の研究を要約し、将来的に答える必要がある問題を特定することである。

Figure 1
Overview of potential health benefits of phytate.

図 1
フィチン酸の潜在的な健康効果の概要。

For this narrative review, available data (from 1960 to today) were searched for in electronic databases such as PubMed, ScienceDirect and Web of Science. Searches were performed for the key words phytic acid, phytate, InsP6, IP6, inositol hexakisphosphate, phytin in combination with Mediterranean diet, DASH diet, calcifications, vascular calcifications, renal lithiasis, lithiasis, urolithiasis, osteoporosis, neurodegeneration, cognitive impairment, diabetes, type 2 diabetes mellitus, cardiovascular health, cardiovascular risk, cancer, breast cancer, anticancer properties, metabolic health and antinutrient.

この叙述的レビューのために、利用可能なデータ(1960年から今日まで)をPubMed、ScienceDirectおよびWeb of Scienceのような電子データベースで検索した。フィチン酸、フィチン酸塩、InsP6、IP6、イノシトールヘキサキスリン酸、フィチンと地中海食事法、DASH食事法、石灰化、血管石灰化、腎結石症、結石症、尿路結石症、骨粗鬆症、神経変性、認知障害、糖尿病、2型糖尿病、心血管系の健康、心血管系リスク、癌、乳癌、抗癌特性、代謝的健康および抗栄養素というキーワードについて検索を行った。

2. Phytate and Vascular Calcification(フィチン酸と血管石灰化)

2.1. Background and In Vitro Studies(背景とインビトロ研究)

Calcifications are crystalline solids made up of calcium in the human body. Some examples include renal lithiasis, dental calculus, chondrocalcinosis, calcinosis cutis and vascular calcifications [3,4,7,8]. The latter one is the result of the formation of hydroxyapatite (HAP) crystals due to excess amounts of calcium and or phosphate [5,6]. This phenomenon can be increased or decreased according to nutrient intake (vitamin D, phytate, lipids, vitamin K, etc.) or by general physical conditions or diseases (low grade inflammation, aging, chronic kidney disease or diabetes). The presence of calcifications in the arterial walls is associated with 3–4 times increased risk of coronary heart disease, stroke and heart failure [6,7,8].

石灰化とは、人間の体内にあるカルシウムが結晶化したものです。例としては、腎結石症、歯石、軟骨石灰沈着症、皮膚石灰沈着症、血管石灰化などがある[3, 4, 7, 8]。後者は過剰量のカルシウムまたはりん酸塩によるヒドロキシアパタイト(HAP)結晶の形成の結果である[5, 6]。この現象は、栄養素の摂取量(ビタミンD、フィチン酸、脂質、ビタミンKなど)や一般的な体調や病気(軽度の炎症、老化、慢性腎臓病、糖尿病)によって増減する可能性があります。動脈壁の石灰化の存在は、冠動脈性心疾患、脳卒中および心不全のリスクを3~4倍増加させる[6, 7, 8]。

Phytate has been demonstrated to inhibit calcium salt crystallization in “in vitro studies” [9]. Thus, some authors have indicated that it colud be taking place either at the nucleation level (adsorption at the surface of the nucleus) or during the subsequent growth or aggregation of the crystals, thus preventing crystallization [4,8]. Moreover, the adsorption of phytate to crystal faces can also inhibit crystal dissolution which partly explains why some agents that prevent pathological calcification, such as phytate, could also inhibit bone decalcification [9].

フィチン酸塩は「in vitro試験」においてカルシウム塩の結晶化を阻害することが示されている[9]。したがって、何人かの著者は、それが核形成レベル(核の表面での吸着)または結晶のその後の成長または凝集の間のいずれかで起こり、したがって結晶化を妨げる可能性があることを指摘している[4, 8]。さらに、フィチン酸塩の結晶面への吸着は結晶溶解を阻害することができ、これはフィチン酸塩のような病的石灰化を防止するいくつかの薬剤が骨の脱灰も阻害することができる理由を部分的に説明する[9]。

2.2. Animal Studies(動物研究)

Grases et al., 2008 [10], conducted a study in male Wistar rats over 66 weeks, which demonstrated that the rats who consumed phytate had significantly lower levels of calcium in the aorta compared with non-phytate rats.

Grases et al., 2008[10]は、雄のWistarラットを用いて66週間にわたる試験を実施し、フィチン酸塩を摂取したラットは、フィチン酸塩を摂取していないラットに比べて大動脈のカルシウム濃度が有意に低いことを実証した。

Two different studies [11,12] used nicotine (generating hypertension) and vitamin D (generating hypercalcemia) to induce calcification in the renal and cardiovascular tissues of male Wistar rats. They developed significant calcium deposits in the kidneys, aorta, and heart; however, rats treated with a moisturizing skin cream containing 2.0% potassium salt of InsP6 had significantly decreased or no deposits in renal papillae, renal interstitium, renal tubules, the aorta and heart [11,12].

２個の異なる試験[11, 12]では、ニコチン(高血圧を引き起こす)およびビタミンD(高カルシウム血症を引き起こす)を用いて、雄のWistarラットの腎臓および心血管組織に石灰化を誘発した。それらは腎臓、大動脈、心臓に有意なカルシウム沈着が認められた；しかしながら、2.0%のInsP6カリウム塩を含有する保湿スキンクリームで処置したラットでは、腎乳頭、腎間質、尿細管、大動脈および心臓の沈着が有意に減少したか、全く認められなかった[11, 12]。

Similar results were obtained by Perelló et al., 2014 [13] in rats in which aggressive cardiovascular calcifications were induced by the administration of high doses of vitamin D. The rats were injected with SNF472 (an intravenous formulation of InsP6) and reductions of aortic and heart calcification by 60 and 70% were seen, respectively. This model was also used to induce calcinosis by Grases et al., 2007 [14] and Ketteler et al., 2013 [15]. The 2007 study used three high doses of vitamin D on Sprague Dawley rats showed that phytate produces a greater reduction in aortic calcium calcifications when compared with rats that had been treated with the placebo or etiodronate [14]. The 2013 study, using a similar study design, compared SNF472 with oral cinacalcet and sodium thiosulfate, proving that SNF472 reduced calcifications by 60% in the aorta and by 68% in myocardial tissue in comparation with a 24% reduction induced by cinacalcet and no reduction at all with sodium thiosulfate [14].

似たような結果はPerello et al., 2014 [13]によって得られ、高用量のビタミンD投与により侵襲性の心血管石灰化が誘発されたラットにSNF472(InsP6の静脈内投与製剤)を注射したところ、大動脈および心臓の石灰化がそれぞれ60および70%減少した。このモデルは、Grases et al., 2007 [14]およびKetteler et al., 2013 [15]によって石灰沈着を誘発するためにも使用された。2007年のSprague Dawleyラットに高用量のビタミンDを投与した試験では、フィチン酸がプラセボまたはエチオドロネートを投与したラットと比較して、大動脈石灰化を大きく減少させることが示された[14]。同様の試験デザインを用いた2013年の試験では、SNF472と経口シナカルセトおよびチオ硫酸ナトリウムを比較し、シナカルセトでは石灰化が24%減少し、チオ硫酸ナトリウムでは全く減少しないのに対し、SNF472では大動脈の石灰化が60%、心筋組織の石灰化が68%減少したことが証明された [14]。

Another model to induce plaque formation is by using subcutaneous injection of 0.1% potassium permanganate (KMnO4) solution [16]. They found that rats treated with a topical application of 2% InsP6 skin cream experienced a significant reduction in plaque size in comparison with the placebo [16]. The urinary levels of phytate in the cream-treated group were significantly higher, showing that topical administration can be an effective route for phytate administration [16].

プラーク形成を誘導する別のモデルは、0.1%過マンガン酸カリウム(KMnO4)溶液の皮下注射を用いることである[16]。2%InsP6スキンクリームを局所塗布したラットは、プラセボと比較してプラークの大きさが有意に減少した[16]。クリーム投与群の尿中フィチン酸濃度は有意に高く、局所投与がフィチン酸投与の有効な経路であることを示している[16]。

Thus, the administration of phytate, whether through the diet, topical skin application or intravenously, has been shown in animal models to be an effective treatment in the reduction in vascular calcification [11,12,13,14,15,16].

このように、フィチン酸塩の投与は、食餌、局所皮膚塗布または静脈内投与のいずれであっても、動物モデルにおいて血管石灰化の減少に有効な治療法であることが示されている[11, 12, 13, 14, 15, 16]。

2.3. Epidemiological Studies in Humans(人間における疫学的研究)

The CAC (coronary artery calcium) score derived from computerized tomography scanning is a validated tool used to assess vascular calcification. The relationship between CAC, cardiovascular risk and mortality has been widely studied in the general population, elderly people, people living with diabetes and patients living with chronic kidney disease with or without dialysis [17,18,19,20,21]. However, the high cost of the technique makes its application to a large amount of the scientific studies difficult.

コンピュータ断層撮影スキャンから得られるCAC(冠動脈カルシウム)スコアは、血管石灰化を評価するために使用される有効なツールである。CACと心血管リスクおよび死亡率との関係は、一般集団、高齢者、糖尿病患者および透析の有無にかかわらず慢性腎臓病患者において広く研究されている[17, 18, 19, 20, 21]。しかし、この技術の高コストは、大量の科学的研究への適用を困難にしている。

Fernández-Palomeque et al., 2015 [22], in a cross-sectional study in a population of 188 elderly subjects, found that subjects with higher levels of urinary phytate had less mitral calcification. Phytate consumption was independently associated with valve calcification.

Fernández-Palomeque et al., 2015 [22]は、高齢被験者188人を対象とした横断研究で、尿中フィチン酸値が高い被験者は僧帽弁石灰化が少ないことを見出した。フィチン酸塩の摂取は弁石灰化と独立して関連していた。

Sanchis et al., 2016 [7], in a prospective cross-sectional study carried out among sixty-nine patients with chronic kidney disease, estimated phytate consumption based on a food frequency questionnaire and quantified abdominal aortic calcification (AAC) using lumbar X-rays. Patients with no/mild AAC were younger, had lower blood pressure, lower prevalence of prior cardiovascular disease, greater dietary phytate intake and greater urinary phytate compared with patients with moderate/severe AAC. Phytate consumption was negatively associated with AAC.

Sanchis et al., 2016 [7]は、慢性腎臓病患者69人を対象とした前向き横断研究で、食物摂取頻度調査票に基づいてフィチン酸塩の摂取量を推定し、腰部X線を用いて腹部大動脈石灰化(AAC)を定量した。非/軽度AAC患者は中等度/重度AAC患者と比較して若く、血圧が低く、以前の心血管疾患の有病率が低く、食事性フィチン酸摂取量が多く、尿中フィチン酸が多かった。フィチン酸塩摂取はAACと負の相関を示した。

Nuts and legumes are a good source of phytic acid (about 1–5% of their weight are phytin) [23]. Lichtensin et al., 2021 [24], in the latest “Dietary Guidance to Improve Cardiovascular Health”, recommended high intakes of legumes and nuts for the prevention of cardiovascular issues. Several studies identified nut intake as a protective factor against cardiovascular disease (CVD), especially for coronary heart disease as well as stroke incidents and stroke mortality [25,26].

ナッツ類と豆類はフィチン酸の良い供給源である(それらの重量の約1–5%がフィチンである)[23]。Lichtensin et al., 2021[24]は、最新の「心血管の健康を改善するための食事ガイドライン」において、心血管疾患の予防のために豆類とナッツ類の大量摂取を推奨している。いくつかの研究は、ナッツ摂取が心血管疾患(CVD)、特に冠動脈性心疾患ならびに脳卒中発症および脳卒中死亡に対する保護因子として同定した[25, 26]。

2.4. Clinical Trials in Humans(人間での臨床試験)

Perelló et al., 2018 [27], enrolled both healthy and hemodialysis patients in the first-in-human, double-blind, randomized, placebo-controlled Phase I study to assess the safety, tolerability and pharmacokinetics of SNF472. Inhibition of the induction of hydroxyapatite crystallization in plasma samples was demonstrable by SNF472. After this first trial, more evidence emerged relating to the role of SNF472 in treating vascular calcification and calciphylaxis in hemodialysis patients [28,29]. SNF472 has completed early-phase clinical trials with a favourable safety profile, and Phase 2 clinical trial data have shown attenuation of coronary artery and aortic valve calcification in patients receiving hemodialysis [30].

Perellóet al., 2018 [27]は、SNF472の安全性、忍容性および薬物動態を評価するために、健常人および血液透析患者の両方を人間初となる二重盲検ランダム化プラセボ対照第I相試験を登録しました。血しょう試料中のヒドロキシアパタイト結晶化の誘導の阻害は、SNF472によって実証されました。この最初の試験の後、血液透析患者における血管石灰化およびカルシフィラキシスの治療におけるSNF472の役割に関するさらなる証拠が明らかになった[28, 29]。SNF472は初期臨床試験を完了し、良好な安全性プロファイルを示し、第2相臨床試験データは血液透析を受けている患者における冠動脈および大動脈弁の石灰化の減弱を示した [30]。

Sanchis et al., 2018 [31] demonstrated in an “in vitro” and “in vivo” randomized crossover trial that consumption of InsP6 inhibits protein glycation in patients with T2DM. Advanced glycation end products (AGEs) and the receptor for advanced glycation end products (RAGE) play pivotal roles in vascular calcification in atherosclerosis [32]. AGEs contribute to microvascular and macrovascular complications in T2DM, in chronic kidney disease, and in aging-related complications [31,32]. The reduction in the production of AGEs could be an effective strategy to reduce vascular calcification.

Sanchis et al., 2018 [31]は、「in vitro」および「in vivo」ランダム化クロスオーバー試験において、InsP6の摂取が２型糖尿病患者のタンパク質糖化を阻害することを実証した。終末糖化産物(AGEs)と終末糖化産物受容体(RAGE)は、アテローム性動脈硬化症における血管石灰化において中心的役割を果たす[32]。AGEは、２型糖尿病、慢性腎臓病、および加齢関連合併症における微小血管および大血管の合併症の一因となる[31, 32]。AGE産生の減少は、血管石灰化を減少させる効果的な戦略である可能性がある。

Estruch et al., 2018 [33], in a multi-centre trial in Spain, enrolled 7447 participants at high cardiovascular risk who were assigned one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet. After a median follow up of 4.8 years, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those in the control diet group. We could hypothesize that part of these benefits could be due to the high phytate content in nuts, and in the Mediterranean diet generally.

Estruch et al., 2018 [33]はスペインの多施設試験で、心血管リスクの高い被験者7447人を対象に、３個の食事法のうち１個を割り当てました：エクストラバージンオリーブオイルを添加した地中海式食事、ミックスナッツを添加した地中海式食事、または対照食。中央値4.8年の追跡調査後、エクストラバージンオリーブオイルまたはナッツを補充した地中海式食事法に割り付けられた患者の主要心血管イベント発生率は、対照食群の患者よりも低かった。これらの利点の一部は、ナッツおよび一般的な地中海料理における高いフィチン酸含量に起因すると仮定することができた。

3. Phytate and Urolithiasis(フィチン酸と尿路結石)

3.1. Background and In Vitro Studies(背景とインビトロ研究)

Urolithiasis, otherwise known as kidney stones or renal calculi, is a multifactorial and highly prevalent urological condition. Its prevalence has increased in recent years and stands at 12% worldwide. In some regions in Europe, its prevalence is as high as 15% [34,35]. Most kidney stones are composed of calcium in the forms of calcium oxalate or calcium phosphate, or a mixture of both, representing 70–80% of the total. Calcium oxalate kidney stones are the most prevalent [34,35]. The process of kidney stone formation is not fully understood. It is thought that crystallization occurs when the concentration of ions exceeds their saturation point in the solution. This would occur when a solution contained a greater amount of dissolved material than could be dissolved by the solvent under normal circumstances [35].

腎臓結石(kidney stone)または腎結石(renal calculi)として知られる尿路結石症は、多因子性で非常に一般的な泌尿器疾患である。有病率は近年増加しており、世界中で12%である。ヨーロッパの一部の地域では、有病率が15%と高い[34, 35]。ほとんどの腎臓結石は、シュウ酸カルシウムまたはリン酸カルシウム、あるいは両方の混合物の形で構成され、全体の70–80%を占める。シュウ酸カルシウム腎結石が最も有病率が高い[34, 35]。腎結石の形成過程は完全には解明されていない。溶液中のイオン濃度が飽和点を超えると結晶化が起こると考えられる。これは、溶液が通常の状況下で溶媒によって溶解されるよりも多量の溶解物質を含む場合に起こる[35]。

As previously mentioned, phytate could inhibit calcium salt crystallization at the nucleation level (adsorption at the surface of the nucleus) or during the growth or aggregation of the crystals, thus preventing crystallisation [9]. Early in vitro work by Grases et al., 1988 [36], showed that the antioxidant action of phytate may play a role in reducing calcium oxalate crystallization. These results were replicated in posterior studies [12,37]. This effect could be enhanced by the addition of magnesium [38].

前述したように、フィチン酸塩はカルシウム塩の結晶化を核形成段階(核表面への吸着)や結晶の成長・凝集過程で阻害し、結晶化を妨げる可能性がある[9]。Grases et al., 1988 [36]による初期のin vitro研究は、フィチン酸の抗酸化作用がシュウ酸カルシウムの結晶化を減少させる役割を果たしている可能性があることを示した。これらの結果は事後研究で再現された[12, 37]。この効果はマグネシウムの添加により増強された[38]。

3.2. Animal Studies(動物研究)

Grases et al., 2004 [39], compared the effectiveness of three different phytate salts in reducing urinary calcium in rats. The most significant results were seen with the use of potassium salt. Phytate intake did not affect levels of urinary oxalate.

Grases et al., 2004 [39]は、ラットの尿中カルシウムの減少における３個の異なるフィチン酸塩の有効性を比較した。最も有意な結果はカリウム塩の使用で見られた。フィチン酸塩の摂取は尿中シュウ酸濃度に影響しなかった。

Grases et al., 2007 [14], induced vascular calcification in 18 male Wistar rats by engendering hypertension and hypercalcemia (using nicotine and vitamin D, respectively) while feeding them with AIN 76-A diet (phytate-free diet). One group was treated with topical skin application of 4 g of a cream containing 2.0% potassium phytate salt, resulting in significant reduction or absence of calcium deposits in kidneys and papillae, as well as in kidney tubules and vessels, compared with non-treated rats. This study showed that phytate acts as a crystallization inhibitor in the intrapapillary tissue and urine. Again, the phytate effect could be enhanced by the addition of magnesium.

Grases et al., 2007 [14]は、18匹の雄WistarラットにAIN76-A飼料(フィチン酸塩を含まない飼料)を与え、高血圧および高カルシウム血症(個々に、ニコチンとビタミンDを使って)を誘発させて血管石灰化を誘発させた。１群では、2.0%フィチン酸カリウム塩を含有するクリーム4gを皮膚に局所塗布し、無処置ラットと比較して、腎臓および乳頭、ならびに腎尿細管および血管におけるカルシウム沈着が有意に減少または消失した。この研究はフィチン酸塩が乳頭内組織と尿中で結晶化阻害剤として作用することを示した。また、フィチン酸塩効果はマグネシウムの添加により増強された。

Different results were reported by Kim et al., 2020 [40] in his most recent study. Four-week-old male and female Sprague Dawley rats were fed AIN-93G (phytate-free diet) supplemented with 0%, 1%, 3%, or 5% phytate for 12 weeks, with a constant supplementation of calcium (Ca2+) concentration. The trial showed that in the AIN-93G diet plus phytate supplementation caused a time and concentration dependent impairment of the renal reabsorption of Ca2+ and phosphate accompanied by parathyroid (PTH) increase, which predisposed to nephrocalcinosis development. In this case, it is very important to consider that the phytate supplement was administered in the form of sodium salt and not calcium-magnesium, which is how it is found in food.

これとは異なる結果がKim et al., 2020 [40]の最新の研究で報告されている。４週齢の雌と雄のSprague Dawleyラットに0%、1%、3%または5%のフィチン酸塩を添加したAIN‐93G(フィチン酸無添加飼料)を12週間与え、カルシウム(Ca`2+́)濃度を一定に添加した。この試験では、AIN‐93G食とフィチン酸塩補給が時間と濃度に、副甲状腺(PTH)の増加によるCa`2+́とリン酸塩の腎臓再吸収の依存性障害を引き起こし、腎石灰化症発症の素因となることを示した。この事例では、フィチン酸サプリメントが食品中に見られるカルシウム-マグネシウムではなく、ナトリウム塩の形で投与されたことを考慮することが非常に重要である。

3.3. Epidemiological Studies(疫学的研究)

The relationship between different dietary factors (liquid intake, pH, calcium, phosphate, oxalate, citrate, phytate, urate and vitamins) and each type of kidney stones has been extensively studied [41]. A general list of recommendations to follow in order to avoid the formation of renal calculi are: daily intake of 2 L water, avoid strict vegetarian diets, avoid excessive animal protein diets, avoid excessive salt (NaCl) consumption, avoid excessive vitamin C and/or vitamin D consumption, avoid exposure to cytotoxic substances and consume phytate-rich products (natural dietary bran, legumes and beans, whole cereals). A considerable number of epidemiological studies have identified a diet rich in phytate as a protective agent in the development of renal calculi [42,43].

様々な食事因子(水分摂取量、pH、カルシウム、リン酸塩、シュウ酸塩、クエン酸塩、フィチン酸塩、尿酸塩、ビタミン)と各タイプの腎臓結石との関係が広範囲に研究されている[41]。腎結石の形成を避けるために従うべき一般的な推奨事項のリストは以下の通りです：毎日２Lの水を摂取すること、厳格な菜食を避けること、過剰な動物性タンパク質の食事を避けること、塩分(NaCl)の過剰摂取を避けること、ビタミンCおよび/またはビタミンDの過剰摂取を避けること、細胞毒性物質への曝露を避けること、およびフィチン酸を豊富に含む製品(天然の食物用ふすま、豆果および豆類、全粒穀物)を摂取すること。相当な数の疫学的研究は、腎結石の発生における予防手段としてフィチン酸塩の豊富な食事を同定した[42, 43]。

The Nurses’ Health Study II [44] is a prospective study that followed 96,245 female participants over the course of eight years, all of whom were young and without any renal calculi history. Dietary habits were assessed using a food frequency questionnaire. Women in the lowest quintile of phytate intake in comparation with the highest quintile had fewer kidney stones. Supplemental calcium intake and a higher intake of animal proteins and sucrose were associated with a higher risk of calcium kidney stones.

Nurses’ Health Study II [44]は、96,245人の女性被験者を8年間にわたって追跡した前向き研究であり、全員が若く、腎結石の既往がなかった。食習慣は食物摂取頻度調査票を用いて評価した。※フィチン酸摂取量が最も低い５分位の女性は、最も高い５分位の女性と比較して腎結石が少なかった。カルシウム補給および動物性蛋白質およびショ糖の高摂取は、カルシウム腎結石の高リスクと関連していた。

※補足
逆のことが書かれている。引用元の研究では「フィチン酸塩の摂取は、結石形成のリスク低下と関連していました。フィチン酸摂取量が最も低い５分位の女性が最も高い５分位の女性と比較して相対リスクが有意であった(腎結石になりやすい)」と記載している。

In a cohort study [45] conducted over the course of one year 165 healthy children aged between five and 12 years old were asked to fill out a dietary questionnaire to determine their dietary habits. Phytate and citrate concentration and excretion were studied in two urine samples (baseline and a 12 h overnight sample) for each child. Low urinary concentrations of phytate and citrate were found in almost one-third of the studied population. These findings suggest that despite children being at low risk of developing kidney stones, diet is a risk factor in their possible development.

１年間にわたって実施されたコホート研究[45]では、5歳から12歳までの165人の健康な子供が、食習慣を究明するために食事アンケートに記入するように依頼された。フィチン酸塩とクエン酸塩の濃度と排泄を、各小児の２個の尿試料(ベースラインと夜通し12時間後の試料)で調べた。尿中フィチン酸塩およびクエン酸塩濃度が低かったのは、調査対象集団のほぼ1/3であった。これらの知見は、小児が腎結石を発症するリスクが低いにもかかわらず、食事が腎結石発症の危険因子であることを示唆する。

The multiple beneficial effects of the Mediterranean diet include a reduced risk of renal calcium salt and uric acid kidney stones. Prieto et al., 2019 [34], in a cross-sectional study in overweight individuals with metabolic syndrome found that good adherence to a Mediterranean diet with a high consumption of fruit, vegetables, legumes and nuts decreased the risk of kidney stones. Moreover, the Dietary Approach to Stop Hypertension (DASH) diet and the Mediterranean style diet have some similarities, particularly in food selection. The DASH diet has also been associated with reduced risk of kidney stones [46,47]. Both diets are high in phytate.

地中海式食事法の複数の有益な効果は、腎臓のカルシウム塩および尿酸腎結石のリスク低下を含みます。Prieto et al., 2019[34]は、メタボリックシンドロームを有する過体重者を対象とした横断研究において、果物、野菜、豆類およびナッツを多量に摂取する地中海食の固守が良好であると、腎結石のリスクが低下することを発見した。さらに、高血圧を予防する食事療法(DASH)と地中海式食事法には、特に食品選択においていくつかの類似点がある。DASH食事法は腎結石のリスク低下とも関連している[46, 47]。両方の食事法もフィチン酸塩を多く含む。

3.4. Clinical Trials in Humans(人間での臨床試験)

Conte et al., 1999 [48], selected three groups of patients with calcium oxalate kidney stones and determined their lithogenic risk through urine tests. Patients with calcium oxalate stones treated with potassium citrate or phytate diet reported a decreased rick on the lithogeny test performed by the authors at the beginning and at the end of the trial. The risk reduction was 52% and 50%, respectively.

Conte et al., 1999 [48]は、シュウ酸カルシウム腎結石患者を３グループに分け、尿検査により結石形成リスクを判定した。クエン酸カリウム食またはフィチン酸塩食による治療を受けたシュウ酸カルシウム結石患者は、試験の開始時および終了時に同著者らが実施した結石形成試験でリスクの減少を報告した。リスク減少はそれぞれ52%および50%であった。

Recently, Guimerà et al., 2022 [49], performed a controlled randomized trial on the effects in humans of daily administration of 380 mg capsule of calcium-magnesium InsP6 on calciuria. The studied population comprised adult patients with urinary stones, hypercalciuria (>250 mg/24 h) and osteopenia or osteoporosis (determined by densitometry) in the femur and/or spine. At 3 months, the phytate group had significantly lower calciuria levels.

最近、Guimeràet al., 2022 [49] は、カルシウム-マグネシウムのInsP6カプセル380mgを毎日人間に投与し、カルシウム尿症に及ぼす影響についてランダム化比較試験を行った。研究対象集団は、尿路結石、高カルシウム尿症(>250mg/24時間)および大腿骨および/または脊椎の骨減少症または骨粗鬆症(濃度測定による判定)の成人患者からなった。３ヶ月後、フィチン酸塩群のカルシウム尿症レベルは有意に低かった。

Besides renal lithiasis, interesting results have been seen in a study administering phytate in a mouthwash solution to 25 healthy dental plaque-forming volunteers [50]. A randomized, double-blind, three-period crossover clinical study showed a statistically significant decrease in calcified dental plaque residues in the phytate-treatment period compared with control and placebo periods. The efficacy of the treatment in the prevention of calculus formation suggests another application of phytate as a crystallization inhibitor.

腎結石症の他に、歯垢を形成している25人の健常ボランティアに洗口液中のフィチン酸塩を投与した研究で興味深い結果が見られた[50]。ランダム化二重盲検３期間クロスオーバー臨床試験では、フィチン酸塩投与群では、対照群およびプラセボ投与群と比較して、石灰化した歯垢の残存が統計学的に有意に減少したことを示した。結石形成の予防における治療の有効性は、結晶化阻害剤としてのフィチン酸塩の別の応用を示唆する。

Clearly, there is an urgent need of more human clinical trials assessing the effect of phytate in preventing and treating kidney stones. In vitro and epidemiological studies showed the efficacy of phytate as a renal calculi inhibitor. It should be borne in mind that there is little treatment available to prevent renal calcification, a prevalent condition.

明らかに、腎臓結石の予防と治療におけるフィチン酸塩の効果を評価する、より多くのヒト臨床試験が緊急に必要である。in vitroおよび疫学的研究で、フィチン酸塩の腎結石阻害剤としての有効性が示された。一般的な状態である腎石灰化を予防するために利用可能な治療はほとんどないことに留意すべきである。

4. Phytate and Osteoporosis(フィチン酸と骨粗しょう症)

4.1. Background and In Vitro Studies(背景とインビトロ研究)

Osteoporosis is a highly prevalent bone disorder especially in post-menopausal women [51]. Lifestyle interventions such as physical activity and nutrition play an important role in the prevention and treatment of bone mineral loss [9,51,52,53].

骨粗鬆症は、特に閉経後女性に多くみられる骨疾患である [51]。身体活動や栄養などのライフスタイルへの介入は、骨ミネラル損失の予防と治療に重要な役割を果たす[9, 51, 52, 53]。

Phytate is an inhibitor of crystallization due to the capacity of binding to the crystal surface. The adsorption of phytate to the crystal faces can inhibit pathological calcifications in vivo and in vitro as mentioned, but can also inhibit hydroxyapatite dissolution and bone resorption [9]. It is important to remark that pyrophosphate and bisphosphonates were discovered previously as inhibitors of both crystal formation and dissolution by binding strongly to HAP crystals. In fact, the bisphosphonates are widely use as drugs for bone mass loss disease [54].

フィチン酸塩は結晶表面への結合の能力により結晶化の阻害剤である。結晶面へのフィチン酸塩の吸着は、上述のようにin vivoおよびin vitroで病理学的石灰化を阻害することができるが、ヒドロキシアパタイトの溶解および骨吸収も阻害することができる[9]。ピロリン酸塩とビスホスホネートがHAP結晶に強く結合することによる結晶形成と溶解の両方の阻害剤として以前に発見されたことに注目することが重要である。実際、ビスホスホネートは骨量減少症の治療薬として広く使用されている [54]。

Phytate has shown the ability in vitro to reduce the osteoclastogenesis of human primary osteoclasts (human peripheral blood mononuclear cell culture (PBMNC) and mouse macrophage RAW264.7 cell lines) [55]. Similar results have been obtained in previous in vitro studies [56,57,58,59]. In a recent in vitro study [9], phytate was able to inhibit acid-driven HAP dissolution. Moreover, the inhibitory effect of phytate on HAP dissolution was greater than that exhibited by etidronate and similar to that of alendronate [9]. Additionally, phytate inhibited HAP dissolution in a concentration-dependent manner [9]. Phytate could help in two opposite processes: to prevent calcification and to decrease bone mass loss [9].

フィチン酸はin vitroでヒト原子破骨細胞 (ヒト末梢血単核細胞培養(PBMNC)およびマウスマクロファージRAW264.7細胞系) の破骨細胞形成を減少させる能力を示した[55]。以前のin vitro試験でも同様の結果が得られている[56, 57, 58, 59]。最近のin vitro試験[9]では、フィチン酸塩は酸によるHAP溶解を阻害することができた。さらに、HAP溶解に対するフィチン酸塩の阻害効果は、エチドロネートによって示されたものよりも大きく、アレンドロネートと同様であった[9]。さらに、フィチン酸塩は濃度依存的にHAP溶解を阻害した[9]。フィチン酸塩は、２個の相反するプロセスに役立つ可能性がある：石灰化を防ぎ、骨量減少を減らすこと[9]。

4.2. Animal Studies(動物研究)

In an animal model study on postmenopausal osteoporosis carried out over 12 weeks on ovariectomized rats, one group was fed with AIN-76A (no phytate diet) and the other group with AIN-76 enriched with 1% phytin. The phytin-consuming group showed an increase in bone mineral density in femoral bones and L4 vertebrae. Phytin reduced the bone density loss caused by estrogen deficiency [60].

卵巣切除ラットで12週間にわたって行われた閉経後骨粗鬆症の動物モデル研究において、あるグループにはAIN‐76A(フィチン酸無添加飼料)を与え、他グループには1%フィチンを濃縮したAIN‐76を与えた。フィチン摂取グループは大腿骨とL4椎骨の骨密度の増加を示した。フィチンはエストロゲン欠乏による骨密度低下を抑制した[60]。

On the other hand, Kim et al., 2020 [40], challenged the previous results. In a study using four-week-old male and female Sprague Dawley rats the systemic effects of dietary phytate were evaluated. Rats were fed AIN-93G diets supplemented with 0%, 1%, 3%, or 5% phytate over 12 weeks with a constant supplementation of calcium concentration. The trial showed that in the AIN-93G diet plus phytate supplementation caused a time and concentration dependent impairment of the renal reabsorption of calcium and phosphate accompanied by PTH increase, predisposing the rats to the development of hypophosphatemic rickets. Once again, it is necessary to consider that these authors used sodium phytate in their study, and not the calcium–magnesium salt, which is the form in which it is found in food.

一方、Kim et al., 2020 [40]はこれまでの結果に異議を唱えた。４週齢の雌雄Sprague Dawleyラットを用いた試験で、食餌性フィチン酸塩の全身作用が評価された。ラットに0%、1%、3%または5%のフィチン酸塩を添加したAIN‐93G飼料を12週間にわたりカルシウム濃度を一定に補給して与えた。この試験では、AIN-93G飼料にフィチン酸塩を添加が時間と濃度に、PTHの増加を伴うカルシウムおよびリン酸塩の腎再吸収の依存性障害を引き起こし、ラットが低リン酸血症性くる病を発症しやすくなることが示された。繰り返しになりますが、ここでも、著者らが研究に用いたのはフィチン酸ナトリウムであり、食品中に含まれるカルシウム-マグネシウム塩ではないことを考慮する必要がある。

4.3. Epidemiological Studies(疫学研究)

The high number of epidemiological studies linking phytate consumption with an improvement of bone health is worth of mention. A descriptive cross-sectional pilot study [61] carried out among 143 postmenopausal women examined the relationship between urinary phytate concentration and risk of fracture within 10 years (using the FRAX model). The risk of major osteoporotic fracture and hip fracture were higher in women with low urinary phytate levels. This difference was higher in women with at least one risk factor for osteoporosis. Similar results were obtained previously by Lopez-González et al., 2013 [62], in a study carried out among 157 postmenopausal women; low InsP6 levels were associated with significantly greater bone mass loss in the lumbar spine and the 10-year fracture probability (calculated by the FRAX model) was also significantly higher in the low-phytate group compared with the high-phytate group, both in hip and major osteoporotic fracture [62]. Moreover, in a prospective study with 1473 subjects they found that the higher the phytate consumption, the greater mineral density [63]. Similar results with a similar design study were found by Lopez-González et al., 2011 [64], where phytate consumption was measured by food questionnaires and bone mineral density was evaluated by dual-X-ray double-energy absorptiometry. The results indicated that adequate phytate consumption may play a significant role in the prevention of bone mineral density loss in postmenopausal women [64].

フィチン酸塩の摂取と骨の健康の改善を結びつける多数の疫学的研究は言及に値する。閉経後女性143人を対象に実施された記述的横断的パイロット研究[61]では、尿中フィチン酸濃度と10年以内の骨折リスクとの関係が調査された(FRAXモデルを使用)。主要な骨粗鬆症性骨折および股関節骨折のリスクは、尿中フィチン酸濃度が低い女性でより高かった。この差は、骨粗鬆症のリスク因子を１個以上有する女性でより高かった。同様の結果は、以前にLopez-González et al., 2013 [62]が157人の閉経後女性を対象に実施した試験で得られている；低いInsP6レベルは腰椎の骨量減少の有意な増大と関連し、(FRAXモデルによって算出した)10年の骨折確率も、低フィチン酸塩群では高フィチン酸塩群と比較して股関節および主要骨粗鬆症性骨折の両方で有意に高かった[62]。さらに、被験者1473名を対象とした前向き研究では、フィチン酸塩の摂取量が多いほど、ミネラル密度が高くなることが見出された[63]。Lopez-Gonzálezet al., 2011 [64]は、同様の設計研究で同様の結果が得られており、フィチン酸塩の摂取量は食物に関する質問票で測定され、骨密度を２重X線２重エネルギー吸収測定法で評価された。その結果は、適切なフィチン酸塩摂取が閉経後女性の骨密度低下の予防に重要な役割を果たしている可能性を示した[64]。

Sanchis et al., 2021 [9], carried out a cross-sectional study in which 415 women completed a validated 14-item questionnaire designed to estimate adherence to the Mediterranean Diet and phytate consumption and where bone mineral density of the L1-L4 was evaluated by dual energy X-ray absorptiometry (DXA). The results showed a significant association between low phytate consumption and low bone mineral density at lumbar spine [9]. According to these data, the ingestion of at least 307 mg/day would prevent bone mineral loss. In a practical sense, this would be highly achievable since the Mediterranean diet is associated with a phytate intake of 1–2 g per day [31,65].

Sanchis et al., 2021 [9]は横断研究を実施し、415人の女性が地中海式食事法およびフィチン酸塩摂取の遵守を推定するために設計された有効な14項目の質問票に回答し、２重エネルギーX線吸収測定法(DXA)によりL1-L4の骨密度を評価した。その結果、フィチン酸塩の摂取量が少ないことと腰椎の骨密度が低いこととの間に有意な関連が認められた[9]。これらのデータによると、少なくとも307mg/日の摂取は骨ミネラルの損失を予防する。地中海式食事法では1日1~2gのフィチン酸塩を摂取するため、実際的な意味では、これは非常に達成可能であろう[31, 65]。

In this sense, the Mediterranean diet has been demonstrated to be an effective method to increase bone mineral density. As mentioned before, diet is a modifiable factor which is crucial to reduce the risk of osteoporosis [66]. The Mediterranean diet, along with other diets such as DASH, is rich in fruits, vegetables, legumes and nuts, all of which are associated with better bone health in epidemiological studies [52,66,67,68].

この意味で、地中海食事法は骨密度を増加させる効果的な方法であることが示されている。前述したように、食事は骨粗鬆症のリスクを低下させるために重要な修正可能な因子である[66]。地中海式食事法は、DASHなどの他の食事法と同様に、果物、野菜、豆類およびナッツ類が豊富であり、その全てが疫学的研究において良好な骨の健康と関連している[52, 66, 67, 68]。

4.4. Clinical Trials in Humans(人間での臨床試験)

As mentioned previously, Guimerà et al., 2022 [49] conducted the first controlled randomized trial on the effects in humans of daily phyate supplementation on bone mineral density (BMD) as a secondary outcome. They used ß-Crosslaps as a serum maker for predicting BMD and the response to antiresorptive treatment. Patients with hypercalciuria (>250 mg/24 h) and osteopenia or osteoporosis (determined by densitometry) in the femur and/or spine who received daily administration of 380 mg capsule of calcium–magnesium InsP6 had significantly lower levels of ß-Crosslaps in comparation with the placebo group after three months of supplementation.

前述のように、Guimeràet al., 2022 [49]は、副次評価項目として骨密度(BMD)に対する毎日のフィチン酸塩補給の効果について、ヒトにおける最初のランダム化比較試験を実施した。BMDおよび骨吸収抑制治療に対する反応を予測する血清マーカーとして、同氏らはß-Crosslapsを使用した。大腿骨および/または脊椎に高カルシウム尿症(>250mg/24時間)および骨減少症または骨粗鬆症(濃度測定で判定)を有し、380mg/日のカルシウム–マグネシウムInsP6カプセルの投与を受けた患者は、補給の３ヵ月後にプラセボ群と比較して、β-Crosslaps値が有意に低かった。

5. Phytate Cognitive Function and Neurodegenerative Disease(フィチン酸認知機能と神経変性疾患)

5.1. Background and In Vitro Studies(背景とインビトロ研究)

Maintaining or achieving normal and optimal cerebral function is a subject of interest for people wishing to increase their cognitive performance (students, workers, athletes, etc.) and wishing to reduce their risk of development of neurodegenerative disease. Cognitive performance and cognitive decline are multifactorial [69]. Physiological processes such as calcium homeostasis, mitochondrial dysfunction, oxidative damage, systemic inflammation, and increased susceptibility to stresses might be hallmarks of cognitive decline [68].

正常かつ最適な脳機能を維持または達成することは、認知能力を向上させたい、そして神経変性疾患の発症リスクを低下させたいと願う人々(学生、労働者、スポーツ選手など)にとって関心の対象である。認知能力と認知機能低下は多因子性である[69]。カルシウム恒常性、ミトコンドリア機能障害、酸化損傷、全身性炎症、ストレスに対する感受性の増加などの生理学的プロセスは、認知機能低下の特徴である可能性がある[68]。

Nutritional choices may play a role in brain health. Food groups (fruits, vegetables, cereals and grains) and nutrients (zinc, selenium, copper, fiber, some vitamins, phytochemicals and polyphenols) have been identified as protective agents against cognitive decline and also cognitive performance enhancers [69,70,71].

栄養の選択は脳の健康に何らかの役割を果たす可能性がある。食品群(果物、野菜、シリアルと穀物)と栄養素(亜鉛、セレン、銅、繊維、一部のビタミン、植物化学物質、ポリフェノール)は、認知低下に対する保護因子として、また認知機能増強剤として同定されている[69, 70, 71]。

Brain tissue is very susceptible to oxidative stress because of the high levels of polyunsaturated fatty acids, low antioxidant concentrations (superoxide dismutase and catalase are lower than in liver tissue) and the high oxidative stress environment [72]. Phytate and the products that result from its metabolism (from InsP5 to InsP2) can exhibit potent antioxidation and anti-inflammatory action. It blocks catalyzed hydroxyl radical (OH-) formation [72,73], inhibits lipid peroxidation [72,74], and minimize iron-related free radical generation, hence mitigating neuronal damage and loss [72,73,74]. Moreover, InsP6 but not InsP3, InsP4 or InsP5 inhibits the activity of amyloid-β precursor protein (BACE1), a protein involved in amyloid-beta accumulation. BACE1 inhibition could prevent Aβ accumulation [75]. All these results have been obtained in in vitro models.

脳組織は、高レベルの多価不飽和脂肪酸、低抗酸化濃度(スーパーオキシドジスムターゼおよびカタラーゼは肝臓組織より低い)および高酸化ストレス環境のため、酸化ストレスに非常に感受性である[72]。フィチン酸およびその代謝産物(InsP5からInsP2へ)は強力な抗酸化および抗炎症作用を示すことができる。それは触媒されたヒドロキシルラジカル(OH-)形成を阻害し[72, 73]、脂質過酸化を阻害し[72, 74]、鉄関連のフリーラジカル生成を最小限にし、それによりニューロン損傷および喪失を軽減する[72, 73, 74]。さらに、InsP3、InsP4またはInsP5ではなくInsP6は、アミロイドβの蓄積に関与する蛋白質であるアミロイドβ前駆体蛋白質(BACE1)の活性を阻害する。BACE1阻害薬はAβの蓄積を防ぐことができる[75]。これらの結果はすべてin vitroモデルで得られた。

5.2. Animal Studies(動物研究)

Phytate can be delivered to the brain. Grases et al., 2007 [76] have demonstrated in a rat model study that phytic acid can cross the blood–brain barrier efficiently, as a ten-fold increase in phytic acid concentrations have been seen in rat brains compared to other tissues after a high phytic acid diet.

フィチン酸塩は脳に送達されることができる。Grases et al., 2007 [76]は、ラットモデルを用いた研究で、フィチン酸を高濃度に摂取したラットの脳では、他の組織に比べてフィチン酸濃度が10倍に増加したことから、フィチン酸が血液脳関門を効率的に通過できることを実証した。

Alzheimer’s disease is a highly prevalent progressive neurodegenerative disorder. Accumulation of beta-amyloid in the brain has been implicated in the physiopathology. Anekonda et al., 2011 [77] evaluated the protective effects of phytate against amyloid beta in Tg2576 mouse model where intraneuronal beta-amyloid accumulation was increased. Over the course of 6 months, female rats were treated with 2% phytic acid drinking water or placebo. No effects from copper, iron and zinc were found on brain levels. Nevertheless, phytate had modest anti-amyloid effects, as well as effects on potentially novel therapeutic targets (SIRT1, PAMPK, autophagy and vesicle proteins). The dose of 2% can be considered rather mild, as legumes, cereals, oil seeds and nuts provide 1–5% phytic acid in the Mediterranean diet. Phytate was also well tolerated. The authors hypothesized that phytate intake mimics caloric restriction, promoting autophagy (activation of the AMPK pathway) and modulating clathrin-coated endocytosis of amyloid-β precursor protein (APP) and its cleavage products.

アルツハイマー病は、高度に蔓延している進行性神経変性疾患です。脳におけるβアミロイドの蓄積は、生理病理学に関与している。Anekonda et al., 2011 [77]は、ニューロン内βアミロイド蓄積が増加したTg2576マウスモデルにおいて、アミロイドβに対するフィチン酸塩の保護作用を評価した。６か月間にわたり、雌ラットに２%フィチン酸飲料水またはプラセボを投与した。銅、鉄、亜鉛の脳への影響は認められなかった。それにもかかわらず、フィチン酸塩は中程度の抗アミロイド効果と潜在的な新規治療標的(SIRT1、PAMPK、オートファジーおよび小胞タンパク質)に対する効果を有した。豆類、穀類、油糧種子、ナッツ類は地中海食事法で1–5%のフィチン酸を供給するので、2%の用量はむしろ穏やかであると考えられる。フィチン酸も忍容性が高かった。著者らは、フィチン酸摂取がカロリー制限を模倣し、オートファジー(AMPK経路の活性化)を促進し、アミロイドβ前駆体蛋白質(APP)およびその分解産物のクラスリン被覆エンドサイトーシスを調節するという仮説を立てた。

Parkinson’s disease is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. Excess iron accumulation has been established as one of the most important histopathological and pathophysiological processes related to Parkinson´s disease. Phytate intake was able to reduce 6-hydroxydopamine (6-OHDA) induced apoptosis in both normal and excess iron conditions in cell culture models [73]. These results were replicated in (6-OHDA)-induced Parkinson´s disease in Wistar rats [74]. Significantly reduced rotations and motor asymmetry in 6-OHDA lesioned rats were seen in the rats that received an oral phytate pre-treatment [74].

パーキンソン病は、アルツハイマー病に次いで２番目に多い神経変性疾患です。過剰の鉄蓄積はパーキンソン病に関連する最も重要な組織病理学的及び病態生理学的プロセスの１個として確立されている。フィチン酸摂取は、細胞培養モデルにおける正常および過剰鉄条件下の両方で、6‐ヒドロキシドーパミン(6‐OHDA)誘導アポトーシスを減少させることができた[73]。これらの結果は、Wistarラットの(6-OHDA)誘発パーキンソン病で再現された[74]。経口フィチン酸塩による前処置を受けたラットでは、6-OHDA損傷ラットにおける有意な回転の減少と運動の非対称性が認められた[74]。

5.3. Epidemiological Studies(疫学的研究)

Diets known to be high in phytate are associated with lower cognitive decline. In a cohort study [78] of 106 patients, who had undergone annual cognitive tests and who had clinical histories of strokes, a food frequency questionnaire was used to find out their dietary habits. Those who followed a diet rich in wholegrains, leafy greens and other vegetables, beans and nuts were found to have had a slower rate of global cognitive decline over an average of 5.9 years of follow-up [78]. This combination of food types is typical of Mediterranean and DASH diets which are also rich in phytates [33,34]. In fact, Van der Brick et al., 2019 [79], in an extensive review, support higher adherence to the Mediterranean diet, DASH diet or a combination of the two as a measure to prevent cognitive decline and Alzheimer´s disease [79].

フィチン酸塩を多く含むことが知られている食事は、認知機能低下の軽減と関連している。年１回の認知機能検査を受け、脳卒中の既往がある患者106人を対象としたコホート研究[78]では、食習慣を知るために食物摂取頻度質問票が用いられた。全粒穀物、葉物野菜、その他の野菜、豆類およびナッツ類を豊富に含む食事を摂取していた被験者は、平均5.9年間の追跡期間中に全般的な認知機能低下の速度が遅いことが判明した[78]。この食品タイプの組み合わせは、フィチン酸塩も豊富な地中海式およびDASH食に典型的である[33, 34]。実際、Van der Brick et al., 2019 [79]は、広範なレビューにおいて、認知機能低下およびアルツハイマー病を予防する手段として、地中海式食事法、DASH食、またはこれらの併用に対する固守の向上を支持している[79]。

The association between phytate intake and prevention of cognitive decline and neurodegenerative disease has been found. Recently, Larvie et al., 2021 [69], used data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES) and the corresponding Food Patterns Equivalents Database (FPED) to study the association of phytate intake and cognitive function. They found that in adults over 60 years old, after controlling other covariants, daily phytate intake was positively associated with cognitive function.

フィチン酸摂取と認知機能低下および神経変性疾患の予防との関連性が見出されている。最近、Larvie et al., 2021 [69]は、2013~2014年の国民健康栄養調査(NHANES)および対応する食品パターン同等物データベース(FPED) のデータを用いて、フィチン酸の摂取量と認知機能との関連を検討した。60歳超の成人では、他の共変量を制御した後、フィチン酸塩の1日摂取量が認知機能と正の関連を示したことを、同研究者らは見出した。

These results were not exclusive to elderly populations. Cormick et al., 2019 [80] followed 835 children between the ages of 6 months and 60 months (five years) in order to find factors that were associated with higher scoring trajectories. Phytate intake had a significant association with higher academic and cognitive performance.

これらの結果は高齢者集団に限ったものではなかった。Cormick et al., 2019 [80]は、高得点の軌跡に関連する因子を見出すために、生後6ヶ月から60ヶ月(５年間)の小児835名を追跡した。フィチン酸摂取は、より高い学業成績および認知能力と有意に関連していた。

5.4. Clinical Trials in Humans(ヒトでの臨床試験)

So far, there is no randomized clinical trial assessing the effect of phytate intake in cognitive decline and neurodegenerative disease.

これまでのところ、認知機能低下および神経変性疾患におけるフィチン酸摂取の効果を評価するランダム化臨床試験はない。

6. Phytate Intake, Type 2 Diabetes Mellitus and Cardiovascular Health(フィチン酸摂取、2型糖尿病、心臓血管の健康)

6.1. Background and In Vitro Studies(背景とインビトロ研究)

T2DM is an endocrine disorder that is characterized by hyperglycemia with alterations in carbohydrate, protein and fat metabolism. Microvascular and macrovascular complications are the main concerns in patients living with poor T2DM control. The 2022 American Diabetes Association Standards of Care focuses on treating T2DM with a metabolic-centric approach and not just a glucose-centric approach [81]. Most of the people living with DM2 are patients with high or very high cardiovascular risk [82]. Controlling hyperglycemia and managing other cardiovascular risk factors would be the goal of the patient centered treatment [81].

T2DM(2型糖尿病)は、炭水化物、蛋白質および脂肪代謝の変化を伴う高血糖を特徴とする内分泌疾患である。微小血管および大血管合併症は、T2DMの制御不良の患者における主な懸念事項である。2022年のアメリカ糖尿病協会の標準治療は、単にグルコース中心のアプローチではなく、代謝中心のアプローチによる治療に焦点を当てている[81]。DM2患者の大半は心血管リスクが高いか非常に高い患者である[82]。高血糖を制御し、他の心血管リスク因子を管理することが、患者中心の治療の目標であろう[81]。

Sustained and uncontrolled hyperglycemia produces changes in cell membrane permeability and transmembrane potential, influencing the relationship of the cell with the environment [83]. Thus, hyperpolarization induces glucose oxidation [84], protein glycation [85,86], activation of the polyol pathway, and increased oxidative stress, leading to a state of low-grade inflammation and pro-oxidative state [83,84,85,86,87].

持続的で制御されていない高血糖は、細胞膜透過性と膜貫通電位の変化を引き起こし、細胞と環境との関係に影響を与える[83]。このように、過分極はグルコース酸化[84]、蛋白質糖化[85, 86]、ポリオール経路の活性化、および酸化ストレスの増加を誘導し、軽度炎症および酸化促進状態[83, 84, 85, 86, 87]の状態につながる。

Phytate intake can play a role in controlling hyperglycemia but, more importantly, also in reducing cardiovascular risk by different mechanisms. Alterations in inositol metabolism (inosituria and inositol intracellular depletion) have been associated in several human and animal studies with hyperglycaemia and insulin resistance [88]. Phytate would reduce oxidative stress by acting as an iron chelator, preventing the generation of iron-driven hydroxyl radical formation and decreasing lipid peroxidation [72,73,74]. InsP6 and the formation of lowers forms (via degradation of InsP6) especially InsP3 play an important role in insulin secretion by regulating calcium-homeostasis [89,90]. Amylase inhibition activity by phytate has been described and would reduce the rate of carbohydrate digestion and absorption [91]. Moreover, phytate could exercise its positive effects too by decreasing leptin and increasing adiponectin levels [89]. On one hand, leptin action promotes an increase in the drive for food, reduced satiety, and energy utilization [88]. On the other hand, higher adiponectin concentrations produce an antioxidant response and are associated with a decreased level of C-reactive protein and interleukin-6 (IL-6) [88].

フィチン酸塩の摂取は高血糖のコントロールに役割を果たすことができるが、より重要なことに、異なる機序による心血管リスクの低下にも関与している。イノシトール代謝の変化(イノシトール尿症およびイノシトール細胞内枯渇)は、数件のヒトおよび動物試験で高血糖およびインスリン抵抗性と関連している[88]。フィチン酸塩は鉄キレート剤として作用し、鉄主導のヒドロキシルラジカル生成を防止し、脂質過酸化を減少させることにより酸化ストレスを減少させる[72, 73, 74]。InsP6および(InsP6の分解を介した)低級形態、特にInsP3の形成は、カルシウム恒常性を調節することによりインスリン分泌に重要な役割を果たす[89, 90]。フィチン酸によるアミラーゼ阻害活性が報告されており、炭水化物の消化吸収速度を低下させると考えられる[91]。さらに、フィチン酸はレプチンを減少させ、アディポネクチンレベルを増加させることによって、プラスの効果を発揮することができる[89]。一方で、レプチンの作用は、食物に対する欲求の増加、満腹感の減少、エネルギー利用を促進する[88]。他方、より高いアディポネクチン濃度は抗酸化反応を生じ、C反応性タンパク質およびインターロイキン-6(IL-6)のレベル低下と関連する[88]。

InsP6 influences lipid metabolism. Researchers have reported a reduction in lipase activity, total cholesterol, low-density lipoprotein, hepatic total lipids, and hepatic triglycerides, whereas increasing high-density lipoprotein levels are also seen in InsP6 supplementation [88]. The salt type of phytate administration will be crucial to the outcome lipid levels. The sodium-phytate form decreases cholesterol concentrations, whereas the calcium–magnesium form can increase cholesterol concentrations [88]. It is hypothesized that the calcium–magnesium form would not bind to bile acids, reducing fecal bile excretion [92].

InsP6は脂質代謝に影響する。研究者らは、リパーゼ活性、総コレステロール、低比重リポタンパク質、肝臓総脂質、肝トリグリセリドの低下を報告しているが、InsP6補充では高比重リポ蛋白値の上昇も見られる[88]。フィチン酸塩投与の塩タイプは結果の脂質レベルに決定的である。フィチン酸ナトリウム型はコレステロール濃度を低下させるが、カルシウム-マグネシウム型はコレステロール濃度を上昇させる可能性がある[88]。カルシウム-マグネシウム型は胆汁酸と結合せず、便中胆汁排泄を減少させるという仮説が立てられている[92]。

Protein glycation leading to the accumulation of AGEs is thought to be one of the main factors triggering the diabetic complications, including nephropathy, retinopathy and neuropathy [92,93,94,95,96,97]. AGE accumulation alters the intracellular signalling and gene expression and releases pro-inflammatory molecules and free radicals [93,94,95,96,97,98]. In fact, proteins are not the only molecules that can produce AGEs as other endogenous components, lipids or nucleic acids can also lead to AGE formation [93,94,95,96,97,98]. Sanchis et al., 2018 [31], showed that InsP6 significantly reduces AGE formation, and in a dose-dependent manner, because InsP6 can strongly chelate Fe3+, preventing the subsequent formation of free radicals [31].

AGEの蓄積をもたらす蛋白質糖化は、腎症、網膜症および神経障害を含む糖尿病合併症を誘発する主要因子の１個であると考えられている[92, 93, 94, 95, 96, 97]。AGE蓄積は細胞内シグナル伝達と遺伝子発現を変化させ、炎症性分子とフリーラジカルを放出する[93, 94, 95, 96, 97, 98]。実際、タンパク質はAGEを産生することができる唯一の分子ではなく、他の内因性成分、脂質または核酸もAGEを産生することができる[93, 94, 95, 96, 97, 98]。Sanchis et al., 2018 [31]は、InsP6がFe3+を強力にキレート化し、その後のフリーラジカルの形成を防ぐことができるため、InsP6がAGE形成を用量依存的に有意に減少させることを示した[31]。

Red cell distribution width (RDW) is a numerical measure of the amount of variability in red blood cell size, which is routinely used in the differential diagnosis of anaemia and has been suggested as a predictor of cardiovascular diseases and anaemia [88]. Inflammation might increase RDW levels through the impairment of iron metabolism [99]. InsP6 could reduce RDW through anti-inflammatory and antioxidant effects [88].

赤血球分布幅(RDW)は赤血球の大きさの変動量の数値的尺度であり、貧血の鑑別診断に日常的に用いられ、心血管疾患および貧血の予測因子として示唆されている[88]。炎症は鉄代謝の障害を介してRDWレベルを増加させる可能性がある[99]。InsP6は抗炎症作用および抗酸化作用を介してRDWを減少させることができた[88]。

Hyperuricemia it is considered a risk factor for cardiovascular events, and it is the most frequent cause of acute arthritis in men [100]. Even countries where the local population had historically low levels of serum uric acid, have experienced an increase in serum uric acid concentration (SUA) due to the acquisition of a Western diet eating pattern [100]. Restricting dietary purine intake should be an effective method for maintaining fasting SUA. However, restricting purine intake in the long term could be difficult [100]. InsP6 has been shown to inhibit purine metabolism in vitro by competitively inhibiting the hydrolysis of purine nucleotides [100]. An overview of the potential cardiovascular bioactivities of phytate can be seen below (Figure 2).

高尿酸血症は心血管イベントの危険因子と考えられており、男性における急性関節炎の最も頻度の高い原因である[100]。地域住民の血清尿酸レベルが歴史的に低かった国でさえ、西洋式の食事パターンの獲得により血清尿酸濃度(SUA)の増加を経験している[100]。食事性プリン体摂取の制限は、空腹時SUAを維持するための効果的な方法である。しかしながら、プリン体摂取を長期的に制限することは困難であろう[100]。InsP6は、プリンヌクレオチドの加水分解を競合的に阻害することにより、in vitroでプリン代謝を阻害することが示されている[100]。フィチン酸塩の潜在的な心血管生物活性の概要を以下に示す(図2)。

Figure 2
Overview of the potential bioactivities in cardiovascular health of phytate.

図２
フィチン酸の心血管系の健康に対する潜在的な生理活性の概要。

6.2. Animal Studies(動物研究)

Dilworth et al., 2005 [89], in a comparative study in rats that were fed phytate plus zinc, phytate alone, zinc alone or placebo, the activities of enzymes involved in carbohydrate and lipid metabolism, as well as transaminases in the liver were assessed. The phytate came from two different sources: phytic acid extracted from sweet potato (Ipomea batatas) or commercial phytic acid. Phytic acid lowered blood glucose (seen with both phytate sources) and increased the activity of glucose-6-phosphate dehydrogenase (this was only seen with phytic acid extracted from sweet potatoes). NADPH generation by glucose-6-phosphate dehydrogenase was used by glutathione reductase to maintain reduced glutathione levels. The promotion of an antioxidant environment could be one of the explanations as to why the up-regulation of the glucose-6-phosphate dehydrogenase activity by phytate could reduce insulin resistance [87]. Similar results were previously found by Onomi et al., 2004 [101], in rats fed a high-sucrose diet. A high-sucrose diet and an amount of phytate ranging from 0.2% to 10% were provided [101]. Rats who ingested 10% sodium phytate experienced a reduction in lipogenic enzymes and lower growth, food intake, serum triglyceride and cholesterol levels, in a dose dependent manner [101]. Lee et al., 2006 [102], reported that diabetic KK mice who were fed purified diets supplemented with different concentrations of sodium phytate (0, 0.5 and 1%) over eight weeks reduced calorie intake, body weight, levels of fasting and random blood glucose, glycated hemoglobin (HbA1c) as well as insulin levels [102].

Dilworth et al., 2005 [89]は、ラットにフィチン酸塩+亜鉛、フィチン酸塩のみ、亜鉛のみ、またはプラセボを投与した比較試験で、肝臓のトランスアミナーゼと同様に、炭水化物および脂質の代謝に関与する酵素の活性を評価した。フィチン酸塩は２個の異なる源から得られた：サツマイモ(Ipomea batatas)から抽出したフィチン酸と市販のフィチン酸。フィチン酸は血糖値を低下させ(両方のフィチン酸源で見られた)、グルコース-6-リン酸デヒドロゲナーゼの活性を増加させた(これはサツマイモから抽出されたフィチン酸でのみ見られた)。グルコース‐6‐リン酸デヒドロゲナーゼによるNADPH生成は、還元型グルタチオンレベルを維持するためにグルタチオン還元酵素により利用された。抗酸化環境の促進は、フィチン酸によるグルコース-6-リン酸デヒドロゲナーゼ活性の上方調節がインスリン抵抗性を低下させる理由の説明の１個である可能性がある[87]。同様の結果は、Onomi et al., 2004 [101]によって高ショ糖飼料を与えたラットですでに発見されている。高ショ糖食と0.2%から10%のフィチン酸塩が与えられた[101]。10%のフィチン酸ナトリウムを摂取したラットは、用量依存的に脂質生成酵素の減少、成長、摂餌量、血清トリグリセリド値およびコレステロール値の低下を経験した[101]。Lee et al., 2006 [102]は、異なる濃度のフィチン酸ナトリウム(0、0.5、および1%)を添加した精製飼料を糖尿病KKマウスに8週間与えたところ、カロリー摂取量、体重、空腹時血糖値、随時血糖値、糖化ヘモグロビン値(HbA1c)、ならびにインスリン値が低下したと報告した[102]。

Phytate can cause inhibition, in a dose-dependent manner, of α-glucosidase and α-amylase activity comparable to standard drug acarbose, in vitro and in rats with streptozotocin–nicotinamide-induced type 2 diabetes mellitus [103]. The antidiabetic function of phytic acid may work in part through the decrease in the activity of intestinal amylase which is indicative of lesser products of carbohydrate digestion formation and subsequently absorption, leading to a decreased percentage spike in random blood glucose [103,104].

フィチン酸は、in vitroおよびストレプトゾトシン-ニコチンアミド誘発２型糖尿病ラットにおいて、標準薬アカルボースと同等のα-グルコシダーゼおよびα-アミラーゼ活性の阻害を用量依存的に引き起こす可能性がある[103]。フィチン酸の抗糖尿病作用は、炭水化物の消化産物の生成とそれに続く吸収の減少を示す腸アミラーゼ活性の低下を介して部分的に作用し、ランダム血糖値のスパイク率を低下させる可能性がある[103, 104]。

A high-fat diet and streptozotocin is a model used to induce T2DM in Sprague Dawley rats. Omoury et al., 2013 [104] used this model to study the effects of the combination of InsP6 and inositol, in comparation with glibenclamide, on several markers of metabolic health over four weeks. The combination of InsP6 and inositol in the mentioned dose achieved better glycemic control (reduced blood glucose plus reduce HOMA-IR index) than glibenclamide. Interestingly, this was the first study to show that leptin levels were increased by phytate [104]. The increased concentration of leptin can explain why, in this study, the rats treated with phytates reduced their food intake by 45%. The effects of phytate intake on lipid metabolism were as expected: reduction in triglycerides and total cholesterol as seen in various works [101,104]. A later study [105], using a very similar approach, found that the increase in serum α-amylase activity in diabetic rats treated with combined InsP6 and inositol or glibenclamide was not significant compared with (that of) the nondiabetic control group. Low serum α-amylase concentrations are associated with pancreatic exocrine-endocrine disorders. The authors hypothesized that the nonsignificant increase in serum α-amylase activity in diabetic rats treated with combined InsP6 and inositol or glibenclamide, compared with the nondiabetic control group, might restore the metabolic abnormalities caused by T2DM. A decreasing trend in the Na+/K+ ATPase activity in the group treated with combined InsP6 and inositol supplement could reduce intestinal carbohydrate absorption. Moreover, in this later study, the authors found that a reduction in RDW levels in the diabetic rats treated with the InsP6 and inositol or glibenclamide can reduce cardiovascular risk.

高脂肪食とストレプトゾトシンはSprague DawleyラットでT2DMを誘導するために使用されるモデルである。Omoury et al., 2013 [104]は、このモデルを用いて、InsP6とイノシトールの組み合わせが代謝的健康のいくつかのマーカーに及ぼす影響を、グリベンクラミドと比較して４週間にわたって研究した。上記用量のInsP6とイノシトールの組み合わせはグリベンクラミドよりも良好な血糖コントロール(血糖低下+HOMA‐IR指数低下)を達成した。興味深いことに、これはレプチンレベルがフィチン酸によって増加することを示した最初の研究であった[104]。レプチン濃度の増加は、この研究でフィチン酸を投与されたラットが摂餌量を45%減少させた理由を説明することができる。フィチン酸塩摂取による脂質代謝への影響は予想通りであり、トリグリセリドと総コレステロールの減少がさまざまな研究で見られた[101, 104]。非常によく似たアプローチを使用した、その後の研究[105]では、InsP6とイノシトールまたはグリベンクラミドを併用投与した糖尿病ラットの血清α-アミラーゼ活性の増加は、非糖尿病対照群と比較して有意ではなかった。低い血清α‐アミラーゼ濃度は膵臓外分泌‐内分泌疾患と関連する。著者らは、InsP6とイノシトールまたはグリベンクラミドの併用投与を受けた糖尿病ラットにおける血清α-アミラーゼ活性の有意ではない上昇が、非糖尿病対照群と比較して、T2DMに起因する代謝異常を回復させる可能性があるという仮説を立てた。InsP6とイノシトールの併用投与群におけるNa+́/K+́ATPase活性の低下傾向は、腸管炭水化物の吸収を低下させる可能性があった。さらに、この後の研究において、InsP6およびイノシトールまたはグリベンクラミドで治療された糖尿病ラットにおけるRDWレベルの低下が心血管リスクを低下させる可能性があることを著者らは見出した。

6.3. Epidemiological Studies in Humans(人間における疫学的研究)

Mediterranean and DASH diets have repeatedly shown their effectiveness in improving glycemic control and decreasing cardiovascular risk. Furthermore, these diets are rich in phytates [33,34]. In the latest “Dietary Guidance to Improve Cardiovascular Health” the Mediterranean diet and the DASH diet are recommended to reduce cardiovascular disease risk (CVD) [24]. The ATTICA study [106] revealed that those who had a higher adherence to a Mediterranean diet improved fasting glucose homeostasis, insulin levels and a lower insulin resistance index (HOMA) in both normoglycemic and diabetic patients [106]. Several works proved that adherence to the Mediterranean diet exerts a protective effect against loss of glycaemic control [106]. These effects on cardiovascular health and glycemic control could be produced by the anti-oxidation and anti-inflammation effects of the Mediterranean diet [107].

地中海食およびDASH食は、血糖コントロールの改善および心血管リスクの低下に有効であることが繰り返し示されている。さらに、これらの食事法にはフィチン酸塩が豊富に含まれている[33, 34]。最新の「心血管の健康改善のための食事ガイドライン」では、地中海式食事法とDASH食が心血管疾患リスク(CVD)を低下させるために推奨されている[24]。ATTICA研究[106]では、地中海式食事法への固守が高い患者は、正常血糖患者と糖尿病患者の両方で空腹時グルコース恒常性、インスリンレベル、低いインスリン抵抗性指数(HOMA)を改善したことが明らかになった[106]。いくつかの研究は、地中海式食事法の遵守が血糖コントロールの喪失に対する保護効果を発揮することを証明した[106]。心血管の健康および血糖コントロールに対するこれらの効果は、地中海式食事の抗酸化作用および抗炎症作用によってもたらされる可能性がある[107]。

In a more specific way, certain foods present in the Mediterranean diet have been investigated in isolation. Several studies proved that a higher intake of legumes and nuts for cardiovascular prevention [24,25,26]. Nuts are identified as a protective factor against cardiovascular disease, especially coronary heart disease and stroke incidence and mortality [22,26]. Improvements in glycaemic control and a reduction in HbA1c were reported as a result of increased dietary intake of legumes and wholegrains [107,108,109]. High intake of dietary fibre, specifically of the soluble type, improves glycaemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations in patients with type 2 diabetes [108].

より具体的な方法では、地中海式食事法に含まれる特定の食品が単独で調査されている。いくつかの研究は、心血管系予防のための豆類とナッツのより高い摂取がそのことを証明した[24, 25, 26]。ナッツ類は心血管疾患、特に冠動脈性心疾患および脳卒中の発生率と死亡率に対する保護因子として同定されている[22, 26]。豆類および全粒穀物の食事摂取量の増加により、血糖コントロールの改善およびHbA1cの低下が報告されている [107, 108, 109] 。特に水溶性食物繊維の大量摂取は、2型糖尿病患者の血糖コントロールを改善し、高インスリン血症を軽減し、血漿脂質濃度を低下させる[108]。

Legumes and whole grains are rich in InsP6 and in fiber; this could explain, to a certain extent, the benefits reported in the scientific literature. Sanchis et al., 2018 [31], mentioned that observational evidence suggests that in the Mediterranean region, the InsP6 consumption is lower in patients with T2DM than in non-diabetic subjects (unpublished data) [31].

豆類と全粒穀物はInsP6と繊維が豊富である；これは、科学文献で報告されている利益をある程度説明することができる。Sanchis et al., 2018 [31]は、地中海地域ではInsP6消費が非糖尿病患者よりもT2DM患者で低いことを示唆する観察的証拠があると述べている(未発表データ)[31]。

6.4. Clinical Trials in Humans(ヒトでの臨床試験)

Most clinicals trials published in this regard investigate the effects of the Mediterranean diet or DASH diet on T2DM or cardiovascular health. The multi-centre, randomized, primary prevention trial of cardiovascular disease (Prevención con Dieta Mediterránea “PREDIMED” Study) [110] in 772 asymptomatic patients, aged between 55 and 80 years of age at high cardiovascular risk, saw improved fasting blood glucose, reduced blood pressure and increased high-density lipoprotein (HDL)/cholesterol ratios in these diets in comparison with a low-fat diet. The participants did not lose weight on either diet [110]. Toobert et al., 2013 [111] tested the effectiveness of the Mediterranean Lifestyle Program (MLP) in 279 post-menopausal women. After six months of intervention a reduction in 0.4% units in HbA1c was reported [111]. In a one-year randomized trial of 259 patients people living with T2DM, a low-carbohydrate Mediterranean diet, a traditional Mediterranean diet, and an American Diabetes Association (ADA)-proposed diet were compared. The low-carb Mediterranean diet and the traditional Mediterranean diet showed better weight loss effects and better reduction in HbA1c compared with the other diet [112].

この点に関して発表されたほとんどの臨床試験は、T2DMまたは心血管の健康に対する地中海食事法またはDASH食の効果を調査している。心血管疾患の一次予防に関する多施設ランダム化試験 (Prevencióncon DietaMediterránea 「PREDIMED」研究) [110]では、心血管リスクの高い55歳~80歳の無症候性患者772人を対象に、低脂肪食と比較して空腹時血糖値の改善、血圧の低下および高密度リポ蛋白(HDL)/コレステロール比の上昇が認められた。参加者はいずれの食事でも体重が減少しなかった[110]。Toobert et al., 2013 [111]は、閉経後女性279人を対象に、地中海式ライフスタイルプログラム(MLP)の有効性を試験した。6ヶ月の介入後、HbA1cの0.4%単位の低下が報告された[111]。２型糖尿病患者259名を対象とした１年間のランダム化試験において、低炭水化物地中海式食事法、伝統的地中海式食事法、およびアメリカ糖尿病協会(ADA)提案の食事法が比較された。低炭水化物地中海食事法および伝統的地中海食事法は、他の食事法と比較して、より良好な減量効果およびHbA1cの低下を示した[112]。

The effectiveness of certain high-phytate foods in improving cardiovascular health has been tested in clinical trials. Recently, 31 people living with T2DM were randomly assigned to two different groups: one designated to consume a legume-free diet, the other to consume a legume-based diet for 8 weeks. Legumes significantly increased serum adiponectin concentrations [113].

特定の高フィチン酸食品が心血管の健康を改善する効果が臨床試験で検証されている。最近、２型糖尿病患者31人が２郡の異なるグループにランダムに割り当てられた：一方は豆類を含まない食事を摂取する群と、他方は豆類ベースの食事を8週間摂取する群。豆類は血清アディポネクチン濃度を有意に増加させた[113]。

Because it is difficult to elucidate or discriminate the effects of phytate from the other components of the diet, clinicals trials using only InsP6 are much needed. In fact, Sanchis et al., 2022 [114] in a randomized crossover trial they provided to people living with T2DM 1 capsule of 380 mg of calcium-magnesium InsP6 twice daily during 12 weeks. When patients received InsP6 supplementation they had significant decrease serum levels of HbA1c and increase adiponectin levels. However, no differences were found in IL-1beta, IL-6 and tumor necrosis tumor necrosis alpha (TNF-alpha). This work proves for the first time that phytate supplementation could increase adiponectin levels in patients living with T2DM.

フィチン酸塩の効果を食事法の他の成分と解明したり区別することは困難であるため、InsP6のみを用いた臨床試験が必要である。実際、Sanchis et al., 2022 [114]は、ランダム化クロスオーバー試験において、2型糖尿病患者にカルシウム-マグネシウムInsP6 380mgのカプセル1錠を1日2回で12週間投与した。InsP6補充を受けた患者は、血清HbA1c値が有意に低下し、アディポネクチン値が上昇した。しかし、IL‐1β、IL‐6および腫瘍壊死α (TNF‐α) には差がなかった。この研究は、フィチン酸補給がT2DM患者のアディポネクチンレベルを増加させることを初めて証明した。

Sanchis et al., 2018 [31] for the first time reported the inhibitory effect of InsP6 on protein glycation, reducing both in vitro and in vivo AGEs in patients living with T2DM. In this randomized cross-over trial [31], 35 patients received either an InsP6 diet (diet plan plus one capsule of 380mg of calcium-magnesium InsP6) or a non-InsP6 diet (the same diet plan without InsP6 supplementation). When the subjects took the InsP6 supplementation, they experienced a reduction of 25% of the levels of circulating AGEs and a 3.8% decline in HbA1c, probably because of reduced overall protein glycation.

Sanchis et al., 2018 [31]は、InsP6のタンパク質糖化に対する阻害作用を、T2DM患者におけるin vitroおよびin vivoのAGEを減少させたことを初めて報告した。このランダム化クロスオーバー試験[31]では、患者35人がInsP6食事法(食事計画にカルシウム-マグネシウムInsP6 380mgカプセル1錠を追加)または非InsP6食事法(InsP6を補充しない同じ食事計画)のいずれかを受けた。被験者がInsP6を補給したところ、彼らは循環AGE値が25%低下し、HbA1c値が3.8%低下を体験した、おそらく全体的なタンパク質の糖化の低下によるものであった。

Ikenaga et al., 2019 [100] in a randomized double-blind placebo-controlled trial assessed the effect of the repeated intake of InsP6 on fasting SUA levels in hyperuricemic subjects, and demonstrated that two weeks of supplementation with twice-daily 600 mg of InsP6 improved fasting SUA levels in these subjects [100].

Ikenaga et al., 2019 [100]は、ランダム化二重盲検プラセボ対照試験において、高尿酸血症の被験者における空腹時SUA値に対するInsP6の反復摂取の効果を評価し、１日２回600mgのInsP6を２週間補給することにより、これらの被験者における空腹時SUA値が改善することを実証した[100]。

7. Phytate Intake and Cancer(フィチン酸摂取と癌)

7.1. Background and In Vitro Studies(背景とインビトロ研究)

Living with overweight or obesity is associated with increased risk (a 11.9% in men and 13.1% in women) for a range of malignancies in at least 13 anatomical sites [115]. Insulin resistance and a poor metabolic profile could lead to low-grade inflammation and oxidative stress, two physiopathological drivers of the association between excess body weight and cancer [115]. Nutrition plays an important role in the prevention and even the treatment of cancer.

過体重または肥満を伴う生活は、少なくとも13の解剖学的部位における一連の悪性腫瘍のリスク増加(男性で11.9%、女性で13.1%)と関連している[115]。インスリン抵抗性および不良な代謝プロファイルは、過剰体重と癌との関連性の２個の生理学的要因である軽度の炎症および酸化ストレスにつながる可能性がある[115]。栄養はがんの予防や治療にも重要な役割を果たします。

Phytate anti-cancer activity is not fully understood [116]. Phytate can reach cancer cells [116]. It is hypothesized that the involvement of lower phosphate inositol phosphates (InsP1-3) in signal transduction pathways can affect the cell cycle regulation, growth, and differentiation of malignant cells [117]. The iron chelation effect and the suppression of hydroxyl formation, explains the antioxidant effect of phytate intake and this could have a role in reducing the low-grade inflammation which is a hallmark of cancer [69,73,117,118].

フィチン酸の抗癌活性は完全には解明されていない[116]。フィチン酸は癌細胞に到達することができる[116]。シグナル伝達経路における低リン酸イノシトールリン酸(InsP1-3)の関与は、悪性細胞の細胞周期調節、増殖、分化に影響を及ぼす可能性があるという仮説が立てられている[117]。鉄キレート化効果とヒドロキシル形成の抑制は、フィチン酸摂取の抗酸化作用を説明し、これは癌の特徴である軽度の炎症を減少させる役割を持つ可能性がある[69, 73, 117, 118]。

Since 1998, the scientific evidence shows that phytate could inhibit pathways involved in malignancy such as cell proliferation and growth, metastasis, angiogenesis, apoptosis and differentiation [118,119,120,121,122]. The effects produced by phytate could benefit patients under chemotherapy treatment by reducing side effects correlated to the treatment, thus improving the patient’s quality of life and even improve long-term survival [117].

1998年以来、科学的証拠は、フィチン酸が細胞増殖と成長、転移、血管新生、アポトーシスおよび分化などの悪性腫瘍に関与する経路を阻害できることを示している[118, 119, 120, 121, 122]。フィチン酸塩によってもたらされる効果は、治療に関連する副作用を減少させることにより、化学療法を受けている患者に利益をもたらし、患者の生活の質を改善し、長期生存率を改善することさえできる[117]。

Phytate has been shown to inhibit the growth of different cell lines in a dose and time dependent manner [117]. This has been seen in hematopoietic cell lines (normal and leukemic) [123,124], in human colon cancer cell lines [119,122], in breast cancer cell lines (estrogen-receptor positive and negative) [125], cervical cancer cell lines [119], in prostate cancer cells [126,127,128], in hepatocarcinoma [129], fibrosarcoma [130] and rabdomyosarcoma [131]. Recently, Markiewicz et al., 2021 [131] investigated the combined effect of phytate and butyrate (PA1B1) on cell lines derived from cancer (HCT116 and HT-29) and healthy (NCM460D) human colonic epithelium. They found that phytate and butyrate together enhanced their pro-apoptotic effect in cancer cells, whereas in the healthy cells phytate suppressed the pro-proliferative action of butyrate and activated a pro-survival pathway [132]. Phytate could exhibit a specificity for cancer cells, being a drug with a selective action [72]. An overview of phytate intake potential benefits on cancer is shown below (Figure 3).

フィチン酸は用量および時間依存的に異なる細胞株の増殖を阻害することが示されている[117]。これは、造血細胞系(正常および白血病)[123, 124]、ヒト結腸癌細胞系[119, 122]、乳癌細胞系(エストロゲン受容体陽性および陰性)[125]、子宮頸癌細胞系[119]、前立腺癌細胞[126, 127, 128]、肝癌[129]、線維肉腫[130]および横紋筋肉腫[131]において見られている。最近、Markiewicz et al., 2021 [131]は、癌由来の細胞株(HCT116およびHT-29)および健康なヒト結腸上皮由来の細胞株(NCM460D)に対するフィチン酸塩および酪酸塩(PA1B1)の複合作用を検討した。彼らは、フィチン酸塩と酪酸塩が共に癌細胞におけるアポトーシス促進作用を増強する一方、健康な細胞ではフィチン酸塩が酪酸塩の増殖促進作用を抑制し、生存促進経路を活性化することを発見した[132]。フィチン酸は癌細胞に対して特異性を示し、選択的作用を有する薬物である[72]。フィチン酸塩摂取が癌に及ぼす潜在的利益の概要を以下に示す(図3)。

Figure 3
Overview of potential beneficial bioactivities of phytate on cancer.

図３
フィチン酸が癌に及ぼす潜在的な有益な生理活性の概要。

7.2. Animal Studies(動物研究)

Phytate effectivity to reduce neoplastic activity has been tested/demonstrated in several animal models. One of the most researched areas is that of colon cancer. Different carcinogens were given to rats and mice, and phytate was administered by food or mixed with water with promising results. Phytate reduces the mitotic rate in the colonic crypts of the animals [133,134,135], and increases chelation of dietary iron, reducing the promotional phase of carcinogenesis [136], and reducing the formation of abnormal crypts [137,138,139], increasing cell apoptosis and differentiation [140,141] and favorably affecting colon morphology [140,141].

腫瘍活性を低下させるフィチン酸の有効性は、いくつかの動物モデルで試験/実証されている。最も研究されている分野の１個は結腸癌である。ラットとマウスに様々な発癌物質を与え、フィチン酸塩を食物または水と混合して投与し、有望な結果を得た。フィチン酸塩は、動物の結腸陰窩における有糸分裂率を低下させ[133, 134, 135]、食餌性鉄のキレート化を増加させ、発癌の促進期を減少させ [136]、異常な陰窩の形成を減少させ[137, 138, 139]、細胞のアポトーシスと分化を増加させ[140, 141]、結腸形態に好ましい影響を与える[140, 141]。

These results were not limited to the colon tissue, as other studies using different experimental models have showed the effectiveness of InsP6 in other tissues. In liver tissue, InsP6 could inhibit tumorigenicity and suppress/regress the growth of HepG2 cells in a transplanted mouse model [142]. Similar results were obtained using a hepatocellular model [143]. In the lungs, phytate showed the reduction in pulmonary carcinogenesis [144,145]. In mammary tissue, some studies reported a 19% reduction in the incidence of mammary carcinoma when InsP6 and inositol were used together [146]. Tumor number, multiplicity and tumor size were also reduced by the use of InsP6 plus inositol [147]. In a skin carcinogenesis model, the animals consuming InsP6 during the initiation stage showed an approximately 50% reduction in the mean number of papilloma per animal [148]. Phytate intake inhibits growth of rhabdomyosarcoma in a dose and time dependent manner. When the study was extended to five weeks, a 49-fold reduction in tumor size was observed in mice treated with InsP6 [131]. For the first time, in 2006, in a trial using in vivo mouse and in vitro human prostate cells, phytate was seen to repress telomerase activity in mouse and human prostate cancer in a dose-dependent manner [149]. It is worth mentioning that, in different studies, phytate effectiveness is reported as dependent on dose, given either before or after the carcinogen administration [117].

これらの結果は、異なる実験モデルを用いた他の研究が他の組織におけるInsP6の有効性を示したように、結腸組織に限定されなかった。肝組織において、InsP6は移植マウスモデルにおいて腫瘍形成性を阻害し、HepG2細胞の増殖を抑制/退縮させることができた[142]。肝細胞モデルを用いても同様の結果が得られた[143]。肺では、フィチン酸塩は肺発癌を減少させた[144, 145]。乳腺組織では、InsP6とイノシトールを併用した場合、乳がんの発生率が19%低下したと報告した研究もある[146]。腫瘍数、多重度および腫瘍サイズもInsP6+イノシトールの使用により減少した[147]。皮膚発がんモデルでは、イニシエーション期にInsP6を摂取した動物は、動物当たりの平均乳頭腫数が約50%減少した[148]。フィチン酸摂取は用量及び時間依存的に横紋筋肉腫の増殖を阻害する。研究が5週間に延長されたところ、InsP6を投与したマウスで腫瘍サイズの49倍の縮小が観察された[131]。2006年に初めて、in vivoマウスおよびin vitroヒト前立腺細胞を用いた試験で、フィチン酸が用量依存的にマウスおよびヒト前立腺癌のテロメラーゼ活性を抑制することが見られた[149]。様々な研究では、フィチン酸塩の有効性は発がん物質投与の前または後に投与された用量に依存すると報告されていることに言及する価値がある[117]。

Phytate is abundant in cereals and legumes. Vucenick et al., 1997 [150], carried out a comparative trial on rats to investigate whether the positive anti-cancer effects reported with high phytate intake were due to the bran intake or the phytate intake. They established five groups: one without phytate (AIN-76 diet); AIN-76A diet containing 5%, 10%, or 20% Kelloggs’ All Bran; the fifth group received 0.4% InsP6 in drinking water (an equivalent to the InsP6 content in 20% bran). Tumor incidence was reduced by 16.7%, 14.6%, and 11.4%, respectively. Only the rats given 0.4% InsP6 in drinking water, equivalent to that in 20% bran, had a 33.5% reduction in tumor incidence, reaching statistical significance. Results showed that the effects were inherent to InsP6 intake [150].

フィチン酸塩は穀類や豆類に豊富に含まれる。Vucenick et al., 1997 [150]は、ラットを用いた比較試験を実施し、フィチン酸塩の大量摂取で報告された抗がん効果が、ふすまの摂取によるものか、フィチン酸塩の摂取によるものかを調べた。彼らは５グループを確立した：フィチン酸を含まないグループ(AIN-76飼料)；Kelloggs’ All Branを5%、10%または20%含有するAIN-76A飼料；第５グループには飲料水中0.4%のInsP6(ふすま中の20%に含まれるInsP6量に相当)を投与した。腫瘍発生率は、それぞれ16.7%、14.6%および11.4%低下した。20%のふすまに相当する0.4%のInsP6を飲水投与したラットのみが腫瘍発生率を33.5%低下させ、統計的に有意であった。結果は、この効果がInsP6摂取に固有であることを示した[150]。

※ふすま
小麦をひいた時にできる皮のくず

7.3. Epidemiological Studies in Humans(ヒトにおける疫学的研究)

Lifestyle interventions are essential in reducing cancer incidence. Although dietary factors are thought to be important in determining the risk of developing cancer, establishing the exact effects of diet on cancer risk has proved challenging [151,152,153,154]. In an umbrella review recently published by Papadimitiu et al., 2021 [155], calcium, dairy, and whole grain products were associated with a lower risk of colorectal cancer [155]. Additionally, the intake of fruits and vegetables were inversely associated with head and neck cancer risk [155]. Some research has showed that the Mediterranean diet, DASH diet and other similar diets have a protective effect against cancer development [151].

生活習慣への介入は、がん発生率の低下に不可欠である。食事因子はがん発症リスクの決定に重要であると考えられているが、がんリスクに対する食事の正確な影響を確立することは困難であることが立証されている[151, 152, 153, 154]。Papadimitiu et al., 2021 [155]が最近発表した包括的レビューでは、カルシウム、乳製品、および全粒穀物製品が結腸直腸癌のリスク低下と関連していた[155]。さらに、果物および野菜の摂取は頭頸部癌リスクと逆相関した[155]。いくつかの研究は、地中海式食事法、DASH食事法および他の類似した食事法には、癌の発生に対する予防効果があることを示している[151]。

The intake of Mediterranean foods (such as fish, vegetables, whole-grains, legumes, nuts, seeds and fruits) contributes to a reduction in the risk of developing cancer, through a series of mechanisms that reduce tumor cell growth, whereas anti-oxidative and anti-inflammatory effects increase chemoprotective effects and inhibit tumor development [151].

地中海食品(魚、野菜、全粒粉、豆類、ナッツ類、種子、果物など)の摂取は、腫瘍細胞の増殖を抑制する一連の機序を介して癌発生リスクの低下に寄与する一方、抗酸化作用および抗炎症作用は化学保護作用を増強し、腫瘍発達を抑制する[151]。

In breast cancer, high adherence to a Mediterranean diet decreases incidence by between 6–20% [156], especially in post-menopausal women [157]. In colorectal cancer, high adherence to Mediterranean diet reduces the risk of colorectal cancer by 30% in men and 45% in women [158]. In prostate cancer, a high adherence to Mediterranean diet was not only inversely associated with a low incidence of prostate cancer, but it was also associated with lower cancer malignancy and mortality rate in patients without metastasis [159,160]. Similar results have been replicated in other malignancies such as gastric cancer [161], bladder cancer [162], head and neck cancer [163], pancreatic cancer [164] and in lung cancer, especially in heavy smokers [165]. It is worth mentioning that being overweight or obese increases estrogen production and hormonal imbalances, heightening the risk of hormonal-related malignancies such as endometrial cancer [166]. The Mediterranean diet weight loss effect could have a role in reducing hormonal-imbalance-related malignancies.

乳がんでは、地中海食事法への高い固守により、特に閉経後女性で[157]、発生率が6–20%低下する[156]。結腸直腸癌では、地中海食への高い固守により結腸直腸癌のリスクが男性で30%、女性で45%低下する[158]。前立腺癌では、地中海食事法への高い固守は、前立腺癌の低い発生率と逆相関するだけでなく、転移のない患者における癌の悪性度および死亡率の低下とも関連していた[159, 160]。同様の結果は、胃がん[161]、膀胱がん[162]、頭頸部がん[163]、膵がん[164]および肺がん、特にヘビースモーカー[165]などの他の悪性腫瘍でも再現されている。過体重または肥満はエストロゲン産生およびホルモン不均衡を増加させ、子宮内膜癌などのホルモン関連悪性腫瘍のリスクを高めることは言及に値する[166]。地中海食事法の減量効果はホルモン不均衡関連の悪性腫瘍の減少に役割を果たす可能性がある。

It is already known that the food matrix may exert a larger effect that any single component of the food by itself [167]. Already in 1985, some authors such as Graf et al. [168] mentioned that high-fibre diets are not always correlated with low frequency of colonic cancer, suggesting the involvement of additional dietary constituents [168]. The authors hypothesized that the antioxidant and anti-inflammatory effects of phytic acid would be responsible for the lower incidence of colorectal cancer, independently of fibre intake.

食物マトリックスは、食物のいかなる単一成分単独よりも大きな影響を及ぼすことがすでに知られている[167]。すでに1985年に、Graf et al. [168]などの研究者が、高繊維食は必ずしも結腸癌の低い発生率と相関しないと述べており、追加の食事成分の関与を示唆します[168]。著者らは、フィチン酸の抗酸化作用および抗炎症作用が、繊維摂取とは無関係に、結腸直腸癌の発生率低下の原因であるとの仮説を立てた。

Some of the foods typically found in the Mediterranean diet have different components in their nutritional matrix that can exert a positive health effect (for example nut, seeds and wholegrains contain omega 3, fibre, phytate, phytochemicals and polyphenols) thus the methodological design of specific studies in the future in order to establish which component exerts which particular effect is an absolute priority.

地中海式食事法に典型的に見られる食品の中には、健康にプラスの影響を及ぼす可能性のある栄養マトリックス中の様々な成分(例えば、ナッツ、種子、全粒穀物は、オメガ3、繊維、フィチン酸塩、植物化学物質とポリフェノールを含む)を有するものがあり、したがって、どの成分がどの特定の効果を発揮するかを確立するための今後の特定の研究の方法論的デザインが絶対的な優先事項である。

7.4. Clinical Trials in Humans(ヒトでの臨床試験)

Cancer treatment has evolved achieving better curation rates and increasing quality of life. However, the overall cure rate remains unsatisfactory. Moreover, the issues caused by the toxicity of oncological drugs remains an issue for the quality of life of cancer patients. New therapeutic options have been introduced to reduce the side effects of cancer treatment. Some nutraceuticals, such as phytate, have been studied as a preventive tool against cancer development, as curative or even as an adjuvant to improve quality of life [169].

癌治療は、より良い根治率と生活の質の向上を達成するために進化してきた。しかしながら、全体的な治癒率は依然として不十分である。さらに、癌治療薬の毒性によって引き起こされる問題は、癌患者の生活の質に対する問題として残っている。がん治療の副作用を軽減するために、新しい治療選択肢が導入されています。フィチン酸などの一部の栄養補助食品は、がん発生に対する予防手段として、治療薬として、さらには生活の質を改善するための補助薬としてさえ研究されている[169]。

In lung cancer, myoinositol but not phytate specifically, in doses ranging from 12 to 30 g/d showed a significant increase in the regression rate of pre-existing dysplastic lesions (phase I [170] and phase IIb [171] studies). The best effects were seen at 18 g, with greater doses showing no further benefits and greater side effects.

肺癌では、フィチン酸ではなくミオイノシトールを12~30g/日の用量で投与すると、既存の異形成病変の退縮率が有意に上昇した(第I相[170]および第IIb相[171]試験) 。最高の効果は18gで認められ、それ以上の用量ではさらなる恩恵は認められず、副作用が増大した。

Breast cancer is the most common malignancy in the female population globally. Both phytate and the combination of phytate and myoinositol have been studied for their potential benefits in the treatment of breast cancer [116,172]. Patients with ductal invasive breast cancer treated with a combination of phytate and inositol in during chemotherapy showed a significantly higher quality of life with higher functional scores compared to placebo groups [172]. Additionally, no leucocyte or platelet drop was observed in the group treated with this nutraceutical combination, outcomes which would be important in order to minimize hematological complications and susceptibility to infections [172]. Proietti et al., 2017 [116], in a double-blind randomized control trial conducted over 6 months, used 200 mg of topical InsP6 in patients with ductal breast cancer stage II-III postoperative (lumpectomy) daily during chemotherapy [116]. This resulted in fewer side effects, fewer postponed chemotherapy cycles and an improvement in the quality of life and functional status in the treatment group. As seen in previous works, white blood cell count remained at normal values in the InsP6 patients, whereas it decreased drastically in the control group [116].

乳癌は世界的に女性集団における最も一般的な悪性腫瘍である。フィチン酸、およびフィチン酸とミオイノシトールの組み合わせは、乳癌の治療における潜在的な有益性について研究されている[116, 172]。化学療法中にフィチン酸とイノシトールの併用療法を受けた乳管浸潤性乳癌患者は、プラセボ群と比較して、有意に高い生活の質と高い機能スコアを示した[172]。さらに、この併用療法群では白血球や血小板の減少は認められなかったが、これは血液学的合併症や感染症に対する感受性を最小限に抑えるために重要な結果である[172]。Proietti et al., 2017 [116]は、6ヵ月にわたって実施された２重盲検ランダム化比較試験において、病期II~IIIの乳管癌術後(乳腺腫瘤摘出術)患者に化学療法中に1日200mgの局所InsP6を使用した[116]。その結果、治療群では副作用が少なく、化学療法サイクルの延期が少なく、QOLおよび機能状態が改善した。以前の研究で見られたように、白血球数はInsP6患者では正常値のままであったが、対照群では劇的に減少した[116]。

Colon cancer is one of the most prevalent cancers in the world. Promising results have been observed in vitro and in animal studies using phytate for colon cancer, firstly, it works as a chemoprotective agent preventing side effects [169] and secondly, it shows an immunostimulant effect on NK-cells, which is linked to a reduction in tumor incidence [173,174]. However, these results have not been confirmed in humans.

結腸癌は世界で最も多い癌の１個である。結腸癌にフィチン酸塩を用いたin vitroおよび動物実験で有望な結果が観察されており、第１に副作用を防ぐ化学保護剤として作用し[169]、第２にNK細胞に対する免疫刺激作用を示し、腫瘍発生率の低下と関連している[173, 174]。しかしながら、これらの結果は人間では確認されていない。

A single case report [175] showed benefits of the combination of phytate and inositol on melanoma. A patient diagnosed with stage IV melanoma declined traditional therapy and instead tried InsP6 and inositol. The patient achieved complete remission and remains in remission 3 years later. These results have not been replicated.

1件の症例報告[175]は、メラノーマに対するフィチン酸塩とイノシトールの組み合わせの有益性を示される。IV期黒色腫と診断された患者が従来の治療を拒否し、代わりにInsP6とイノシトールを試した。患者は完全寛解を達成し、3年後も寛解を維持している。これらの結果は再現されていない。

8. Other Phytate Applications(その他のフィチン酸の用途)

The increased prevalence of antibiotic resistance is a public health issue that makes finding natural ingredients capable of reducing/inhibiting microbiological activity crucial. Phytate has shown its antibacterial properties in vitro on Enterococcus faecalis [176], Escherichia coli O157:H7 [177] and in Bacillus Subtilis [178]. Although the mechanism it is not fully known, the weak acid theory could explain the disruptive effects of phytic acid on the cytoplasm and pH homeostasis [137].

抗生物質耐性の増加した有病率は、微生物活性を減少/阻害できる天然成分の発見を重要にする公衆衛生問題である。フィチン酸は、Enterococcus faecalis [176]、Escherichia coli O157:H7 [177およびBacillus Subtilis [178]に対してin vitroで抗菌性を示した。そのメカニズムは完全にはわかっていないが、弱酸説はフィチン酸の細胞質とpH恒常性に対する破壊的効果を説明することができる [137]。

Phytic acid has shown in vitro antiviral effect. Phytate inhibited the cytopathic effect of human immunodeficiency virus, leading to the hypothesis that it may act on early replicative stages [179].

フィチン酸はin vitroで抗ウイルス作用を示した。フィチン酸はヒト免疫不全ウイルスの細胞変性作用を阻害したことから、初期の複製段階に作用するのではないかという仮説につながった[179]。

Biscuits enriched with InsP6 [4], capsules containing phytin in order to prevent lithiasis and a mouth wash for plaque prevention [4] are all available on the market.

InsP6を豊富にしたビスケット[4]、結石症を予防するためのフィチン含有カプセル、歯垢予防のための口内洗浄液[4]はすべて市販されている。

Studies in basic and translational research have revealed the role of AGEs in the development and progression of various age-related pathological conditions [180]. Sanchis et al., 2018 [31], showed that a three month InsP6 diet significantly lowered the levels of circulating AGEs (~25%) in patients with T2DM. This effect is likely to be explained by InsP6-mediated chelation of Fe3+ [31].

基礎研究およびトランスレーショナルリサーチの研究により、様々な加齢に伴う病態の発症および進行におけるAGEの役割が明らかにされている[180]。Sanchisら (2018) [31]は、３ヶ月間のInsP6食が２型糖尿病患者の循環AGEレベルを有意に低下させたことを示した(~25%)。この効果はInsP6が媒介するFe3+́のキレート化によって説明されるようである[31]。

Phytate may have application in the food security industry. Some research has shown that it could be recommended as a food additive which prolongs the stability of both raw and cooked meat, to a larger degree when it is cooked [181]. Moreover, adding InsP6 to wine and other beverages would reduce the side effects and toxicity of high metal content in beverages [182]. The pharmaceutical industry tested the addition of InsP6 to drugs on rats and showed that it was able to improve drug absorption and increase oral bioavailability [183]. In dentistry, InsP6 has attracted attention, due to antimicrobial action producing a caries-preventive effect [184]. It has also demonstrated the ability to bind to hydroxyapatite, forming a monomolecular surface layer that limited both the growth and dissolution of HAP crystals, thus inhibiting caries, plaque formation and enamel dissolution [185]. These findings have led to the development of several patented oral care regimes [185].

フィチン酸塩は食品安全産業に応用できる可能性がある。いくつかの研究では、生肉と加熱調理された肉の両方の安定性を、加熱調理された場合にはより大きく延長する食品添加物として推奨できることが示されている[181]。さらに、ワインや他の飲料へのInsP6の添加は、飲料中の高金属含有量の副作用と毒性を低減するであろう[182]。製薬業界はラットでInsP6の薬物への添加を試験し、それが薬物吸収を改善し、経口生物学的利用能を増加させることができることを示した[183]。歯科分野では、虫歯予防効果をもたらす抗菌作用が注目されている[184]。ヒドロキシアパタイトに結合する能力も実証されており、HAP結晶の成長と溶解の両方を制限する単分子表面層を形成し、齲蝕、プラーク形成およびエナメル質溶解を阻害する[185]。これらの知見は、いくつかの特許取得済みの口腔ケア計画の開発につながった[185]。

9. Controversies of Phytate Intake(フィチン酸摂取に関する議論)

Bioavailability is a measure of the amount of absorption and supply to cells and organs of nutrients (micronutrients and macronutrients). Any reduction in the bioavailability of nutrients can affect our health. Our bodies do not have endophytase; therefore, phytate cannot be broken down by the human body [186]. Thus, the minerals chelated in phytate are not bioavailable. This finding has led to phytate being tagged as an “anti-nutrient”. Nevertheless, this effect can be reversed by phytase-induced degradation of phytic acid during food processing (by means of phytases present in the plant/flour) as well as during digestion (by phytase activity expressed in microbiota residing in the intestinal tract) [187]. Other techniques are also effective in reducing phytate content [188] as cooking at 95° for one hour reduce phytate content between 11–80% [188], soaking reduce phytate content between 17–80% and sprouting reduce phytate content more than 60% [188].

生物学的利用能は、栄養素(微量栄養素および多量栄養素)の細胞および臓器への吸収量と供給量の尺度である。栄養素の生物学的利用能のいかなる減少も私たちの健康に影響を及ぼす可能性がある。私たちの体にはエンドフィターゼがありません；したがって、フィチン酸塩は人体で分解されない[186]。したがって、フィチン酸塩中でキレート化されたミネラルは生物学的に利用できない。この発見により、フィチン酸塩は「抗栄養素」と分類されるようになった。それにもかかわらず、この影響は、食品加工中(植物/小麦粉に存在するフィターゼによる)および消化中(腸管に存在する微生物叢に発現するフィターゼ活性による)にフィターゼが誘導するフィチン酸の分解によって逆転することができる[187]。他の技術もフィチン酸含量を減らすのに有効である[188]、95°Cで１時間調理するとフィチン酸含量が11–80%減少し[188]、浸漬するとフィチン酸含量が17–80%減少し、発芽させるとフィチン酸含量が60%以上減少する[188]。

Several studies showed that phytate intake could reduce mineral bioavailability, especially iron absorption [23,189]. As mentioned by Brouns, 2022, the results in vivo can differ from those obtained in vitro. A decrease in soluble minerals in vitro does not necessarily translate into an increase in bioavailability in vivo because other environmental/dietary factors may play a role [187].

いくつかの研究は、フィチン酸塩の摂取がミネラルの生物学的利用能、特に鉄吸収を低下させる可能性があることを示した[23, 189]。Brouns(2022)によって述べられているように、in vivoでの結果はin vitroで得られた結果と異なることがある。in vitroでの可溶性ミネラルの減少は、他の環境/食事因子が関与している可能性があるため、必ずしもin vivoでのバイオアベイラビリティの増加につながるとは限らない[187]。

The bioavailability of minerals can be calculated according to the phytate:mineral ratio [188]. The optimal ratio of phyate/mineral could be lower than 0.4:1 (phyate:iron) [190], higher than 15:1 (phyate:zinc) [191] and higher than 0.17:1 (phyate:calcium) [192]. The interaction between phytate and other nutrients must be mentioned. Miller et al. reported that the effect of dietary phytate on zinc absorption when controlling for dietary zinc was very small and not statistically discernable [193]. Additionally, Hope et al., 2019 [194], in a 12-week, randomized, parallel study in humans, compared two different wholegrain bread formulations. One of them contained high phytate content and the other one, low phytate content. The difference in phytate content did not impact iron status. Other researchers observed similar results on iron metabolism when comparing the effect of genetically modified maize containing 30–50% less phytic acid versus regular maize [195,196]. Several human trials indicated too that phytate intake of 2 g per day did not affect mineral balance [31,197,198,199].

ミネラルの生物学的利用能はフィチン酸塩：ミネラル比によって計算できる[188]。フィアート/ミネラルの最適比は0.4：1 (フィチン酸：鉄) 以下[190]、15：1 (フィチン酸：亜鉛)以上[191]、0.17：1(フィチン酸：カルシウム)以上[192]であった。フィチン酸と他の栄養素との相互作用についても言及しなければならない。Millerらは、食事性亜鉛を調整した場合、フィチン酸塩が亜鉛吸収に及ぼす影響は非常に小さく、統計的に識別できないと報告した[193]。さらに、Hope et al., 2019 [194]は、人間における12週間のランダム化並行研究で、２個の異なる全粒粉パン製剤を比較した。一方はフィチン酸含量が高く、他方はフィチン酸含量が低かった。フィチン酸含量の差は鉄の状態に影響しなかった。他の研究者は、フィチン酸が30–50%少ない遺伝子組換えトウモロコシと通常のトウモロコシを比較して、鉄代謝に関して同様の結果を観察した[195, 196]。ヒトを対象とした数件の試験でも、1日2gのフィチン酸塩摂取はミネラルバランスに影響しないことが示された[31, 197, 198, 199]。

The dose and route of administration of phytate are highly variable in the different available in in vivo (animal and humans) studies. The administration of phytate and their benefits are associated with the appearance of InsP6 and its phosphorilated inositols (InsP5, InsP4, InsP3 and InsP2) in the urine [8]. Otherwise, in the absence of oral or topical phytate, only InsP2 is quantifiable in the urine [8]. The best available option to measure InsP6 and their dephosphorylation products in urine are coupling high liquid performance chromoatography (HLPC) with mass spectrometry (MS) [8]. In rats, the administration of topical or oral phytate produce an elevation of phytate and their dephosphorylated products in urine [200,201]. These elevation lasts for 22 days after the cessation of phytate supplementation [200,202]. When healthy volunteers received a high phytate they experienced an increase in urinary excretion of total InsPs that return to baseline levels in 16 days after the cessation of high phytate intake [202]. Thus, the topical or the oral supplementation of InsP6 produced an increased urinary excretion of total InsPs in animals and in humans [8]. However, as Grases et al., 2019 [8], mentioned, many aspects of the chemical analysis of InsPs require further work and it would be very interesting to develop specific analytical method for quantification phytate and the products which result from its dephosphorylation.

フィチン酸塩の用量および投与経路は、in vivo(動物および人間)試験で利用可能な様々な試験において非常に多様である。フィチン酸塩の投与とその効果は、InsP6とそのリン酸化イノシトール(InsP5、InsP4、InsP3、およびInsP2)の尿中への出現と関連している[8]。そうでなければ、経口または局所フィチン酸塩が存在しない場合、InsP2のみが尿中で定量可能である[8]。尿中のInsP6とその脱リン酸化生成物を測定するための最良の利用可能な選択肢は、高速液体クロマトグラフィー(HLPC)と質量分析(MS)を組み合わせることである[8]。ラットでは、フィチン酸塩を局所または経口投与すると、尿中のフィチン酸塩とその脱リン酸生成物が増加する[200, 201]。これらの上昇はフィチン酸塩補給中止後22日間持続する[200, 202]。健康なボランティアが高フィチン酸塩を摂取すると、総InsPの尿中排泄量が増加し、高フィチン酸塩摂取中止後16日でベースライン値に戻った[202]。このように、InsP6の局所または経口補給は、動物およびヒトにおける総InsPの尿中排泄を増加させた[8]。しかし、Grases et al., 2019 [8]が述べているように、InsPの化学分析の多くの側面はさらなる研究を必要としており、フィチン酸塩とその脱リン酸化から生じる産物を定量するための特異的な分析法を開発することは非常に興味深い。

Despite the idea that InsP6, due to its high charge density, could not cross the lipid bilayer of cellular membranes [203], Grases et al., 2005, showed the penetrance of phytate in multiple tissues (kidney, brain, bone, plasma and urine) [204]. In fact, the majority of InsP6 present in the organism is of dietary origin and its endogenous synthesis is not important [204]. Moreover, when dietary phytate intake is increased, an elevation in the urine of phytate and its dephosphorylated products is shown, in rats and in humans [8,197,200,201,202]. In fact, the entry of phytate and its derivates through the intestine is believed to be paracellular, as in the case of bisphosphonates, and for this reason the rate of absorption is low. Ferry et al., 2002 [119], in a study examining HeLa cells culture, suggested that InsP6 could enter the cells pinocytotically and then being further dephosphorylated into lower InsPs derivates. Thus, the evidence shows the absorption of InP6 exists in different tissues, although the specific mechanism which InsP6 enters the cell require further work.

InsP6はその高い電荷密度のために細胞膜の脂質二重層を通過できないという考えにもかかわらず(腎臓、脳、骨、血漿、尿)[203]、Grases et al., 2005に複数の組織におけるフィチン酸の浸透を示した[204]。実際、生体内に存在するInsP6の大部分は食物由来であり、その内因性合成は重要ではない[204]。さらに、食餌性フィチン酸塩の摂取量が増加すると、ラットとヒトでフィチン酸塩とその脱リン酸化産物の尿中濃度が上昇することが示されている[8, 197, 200, 201, 202]。実際、フィチン酸とその誘導体は、ビスフォスフォネートの場合と同様に腸から傍細胞に入ると考えられており、このため吸収率は低い。Ferry et al., 2002 [119]は、HeLa細胞培養を検討した試験において、InsP6が飲食的に細胞に入り、その後さらに脱リン酸化されてより低いInsP誘導体になることを示唆した。このように、InP6の吸収が異なる組織に存在することを示す証拠があるが、InsP6が細胞に入る特異的なメカニズムについては更なる研究が必要である。

The effectivity of phytate intake seen in in vivo, animal and epidemiological data has revealed the need for well-designed human clinical trials to assess the effectivity of phytate intake in vascular calcifications, urolithiasis, osteoporosis, cognitive function, metabolic health and cancer. In Table 1, we show all the clinical trials performed in humans using phytate.

in vivo、動物および疫学的データで見られるフィチン酸摂取の有効性は、血管石灰化、尿路結石症、骨粗鬆症、認知機能、代謝的健康および癌におけるフィチン酸摂取の有効性を評価するための適切にデザインされたヒト臨床試験の必要性を明らかにした。表1に、フィチン酸塩を用いてヒトで実施されたすべての臨床試験を示す。

Table 1

Phytate Intake, Health and Disease: “Let Thy Food Be Thy Medicine and Medicine Be Thy Food”

10. Conclusions

In this review, we have summarized the benefits of phytate on health and we identified questions to answer in the future (Figure 4). In a structured way, we have shown the effects of phytate on vascular calcifications, urolithiasis, osteoporosis, cognitive function, metabolic health, cancer and some potential applications. These are our take-home messages:
・It is well known that phytate is a powerful agent for preventing calcifications in biological fluids: usefulness in renal lithiasis treatment, sialolithiasis and vascular calcifications.
・Phytate can also avoid or disturb loss of bone mass. Low doses of phytate could generate a strongly protective effect as we have seen in osteoporosis where a minimum of 307 mg/day of phytate (1–2 servings of nuts or legumes per day) reduce the risk of osteoporosis.
・Phytate has shown benefits in reducing leptin levels, increasing adiponectin, improving carbohydrate and lipid metabolism, decreasing AGEs (the potential reduction in microvascular and macrovascular diabetes-related complications and aging), improving anti-inflammatory and antioxidant effects and improving quality of life during chemotherapy.
・There is no pharmacological intervention available that directly reduces neurological decline, vascular calcifications, and urolithiasis. Phytate has shown effectivity in these regards in in vitro, animal, and epidemiological data.
・Recommending a diet high in phytate such as the Mediterranean diet or DASH diet can exert multiple health benefits with no harm.
・The effectivity of phytate intake seen in in vivo, animal and epidemiological data has revealed the need for well-designed human clinical trials to assess the effectivity of phytate intake in vascular calcifications, urolithiasis, osteoporosis, cognitive function, metabolic health and cancer. Phytate intake or phytate-based drugs/supplements should be investigated further.

このレビューでは、フィチン酸塩の健康効果をまとめ、今後の課題を明らかにしました(図4)。構造化した方法で、血管石灰化、尿路結石症、骨粗鬆症、認知機能、代謝健康、癌およびいくつかの潜在的応用に対するフィチン酸塩の効果を示した。これらは、私たちの重要なメッセージです：
・フィチン酸塩は体液中の石灰化を防止する強力な薬剤であり、腎結石症治療、唾石症および血管石灰化における有用性がよく知られている。
・フィチン酸塩は骨量の減少を防いだり妨げたりすることもあります。骨粗鬆症で見られたように、低用量のフィチン酸塩は強力な予防効果を発揮する可能性があり、少なくとも307mg/日のフィチン酸塩(ナッツまたは豆類を1日1–2人分)が骨粗鬆症のリスクを低下させる。
・フィチン酸塩は、レプチンレベルの低下、アディポネクチンの増加、炭水化物および脂質代謝の改善、AGEの低下(微小血管および大血管の糖尿病関連合併症および老化の潜在的減少)、抗炎症作用および抗酸化作用の改善、ならびに化学療法中の生活の質の改善に有益であることが示されている。
・神経学的低下、血管石灰化、尿路結石症を直接減少させる薬理学的介入はない。フィチン酸塩はin vitro、動物および疫学的データにおいてこれらの点で有効性を示した。
・地中海食事法やDASH食などのフィチン酸塩を多く含む食事を推奨することは、害を及ぼすことなく複数の健康上の利益をもたらす可能性がある。
・in vivo、動物および疫学的データで見られるフィチン酸摂取の有効性は、血管石灰化、尿路結石症、骨粗鬆症、認知機能、代謝的健康および癌におけるフィチン酸摂取の有効性を評価するための適切にデザインされたヒト臨床試験の必要性を明らかにした。フィチン酸塩の摂取またはフィチン酸塩ベースの薬剤/サプリメントをさらに調査すべきである。

Figure 4
Benefits and questions to answer about phytate intake.

図４
フィチン酸摂取の利点と答えるべき質問。

Funding Statement

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions

Conceptualization, A.P., P.S. and L.M.; methodology, A.P., P.S., F.G. and L.M., writing—original draft preparation A.P. and L.M.; writing—review and editing A.P., P.S., F.G. and L.M. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

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