JP2004262927A - Serum cholesterol-reducing agent, food or drink, and method for producing the same - Google Patents
Serum cholesterol-reducing agent, food or drink, and method for producing the same Download PDFInfo
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- JP2004262927A JP2004262927A JP2004034129A JP2004034129A JP2004262927A JP 2004262927 A JP2004262927 A JP 2004262927A JP 2004034129 A JP2004034129 A JP 2004034129A JP 2004034129 A JP2004034129 A JP 2004034129A JP 2004262927 A JP2004262927 A JP 2004262927A
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- gcg
- catechins
- cholesterol
- ecg
- egcg
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Abstract
Description
本発明は、血清コレステロール値を低下させる作用を備えた薬剤及び飲食物、これらの製造方法に関する。 The present invention relates to drugs, foods and drinks having an effect of lowering serum cholesterol levels, and methods for producing them.
血清コレステロールの高値は、高脂血症、肥満、動脈硬化、血栓症などを誘因するばかりか、脳梗塞や心筋梗塞、動脈硬化などの原因ともなることが知られるようになり、血清コレステロール、特に総コレステロール値や悪玉と呼ばれるＬＤＬ−コレステロールの値は、今や現代人が最も注意する健康指標の一つとなっている。 High serum cholesterol not only causes hyperlipidemia, obesity, arteriosclerosis, thrombosis, etc., but also becomes known to cause cerebral infarction and myocardial infarction, arteriosclerosis, etc., serum cholesterol, especially Total cholesterol level and LDL-cholesterol level, which is called bad, are now one of the most important health indicators of modern people.
ところで、食品に含まれるコレステロールは、腸内に分泌された胆汁酸の働きにより胆汁酸ミセルという非常に小さい親水性の分子に取り込まれて腸管から吸収されることが知られている。したがって、食品が摂取されてから胆汁酸ミセルに取り込まれるまでのいずれかの過程でコレステロールの吸収を阻害することができれば、コレステロールの上昇を抑制することができる。このような観点から、様々な物質について様々な作用機序が報告・提案がなされており、中でも、天然物である茶抽出成分には数多くの報告がなされている。 By the way, it is known that cholesterol contained in food is taken up by extremely small hydrophilic molecules called bile acid micelles and absorbed from the intestinal tract by the action of bile acids secreted into the intestine. Therefore, if the absorption of cholesterol can be inhibited in any process from the ingestion of the food to the incorporation into the bile acid micelles, the increase in cholesterol can be suppressed. From such a viewpoint, various mechanisms of action have been reported and proposed for various substances, and in particular, many reports have been made on tea extract components, which are natural products.
例えば、特許文献１は、茶葉中に含まれる（−）エピカテキン（ＥＣ）に血中コレステロール量低下作用がある旨を開示し、特許文献２は、茶カテキン類、中でも特に（−）エピガロカテキンガレート（ＥＧＣｇ）を有効成分とするコレステロール低下剤を開示し、特許文献３は、（−）エピガロカテキンガレート（ＥＧＣｇ）又は（−）エピカテキンガレート（ＥＣｇ）を有効成分とする抗高コレステロール血症剤を開示し、特許文献４は、エピカテキンガレート（ＥＣｇ）を有効成分とするコレステロール排泄促進剤を開示している。
For example, Patent Literature 1 discloses that (-) epicatechin (EC) contained in tea leaves has a blood cholesterol lowering effect, and
また、静岡大学の村松敬一郎名誉教授らは、実験動物としてラットを用い、高脂・高コレステロール食若しくはコレステロール無添加食を投与した実験で、茶カテキン混合物（純度９１．２％、相対カテキン含量（％）；（−）ＥＧＣｇ：（−）ＥＧＣ：（−）ＥＣｇ：（−）ＥＣ＝５８：１７：１５：１０）及び（−）ＥＧＣｇには、血漿総コレステロール濃度及びＬＤＬ−コレステロール濃度の低下効果が認められる一方、血漿ＨＤＬ−コレステロールやＬＤＬ−コレステロールを正常レベル以下に下げる作用はない旨を報告している（非特許文献１）。 Also, Keiichiro Muramatsu, Professor Emeritus of Shizuoka University, conducted experiments using rats as experimental animals and administered a high fat / high cholesterol diet or a cholesterol-free diet, in a tea catechin mixture (purity 91.2%, relative catechin content ( %); (−) EGCg: (−) EGC: (−) ECg: (−) EC = 58: 17: 15: 10) and (−) EGCg include decreased plasma total cholesterol and LDL-cholesterol levels. It has been reported that while it has an effect, it has no effect of lowering plasma HDL-cholesterol or LDL-cholesterol below normal levels (Non-Patent Document 1).
他方、茶抽出物成分の作用機序に関しては、茶、赤ワイン等に含まれるポリフェノールの一種の高コレステロール血症予防作用は、ポリフェノール類が腸肝循環における胆汁酸のミセル形成を阻害し、コレステロールの再吸収を妨害することによって発現することが示唆されている（非特許文献２）。 On the other hand, regarding the mechanism of action of the tea extract components, a preventive action of hypercholesterolemia, a kind of polyphenol contained in tea, red wine, etc., is based on the fact that polyphenols inhibit micelle formation of bile acids in enterohepatic circulation, It has been suggested that it is expressed by interfering with reabsorption (Non-Patent Document 2).
また、茶カテキン（ＥＧＣｇ）の共存により、コレステロールの小腸粘膜への吸収が濃度依存的に抑制された旨の報告（非特許文献３）や、ＥＧＣｇやＥＣｇが混合ミセル中のコレステロールの溶解性を低下させ、これが腸管よりのコレステロール吸収抑制の原因をなす旨の報告（非特許文献４）、更には、ＥＧＣｇやＥＣｇがコレステロール生合成の律速酵素の１つであるスクアレンエポキシダーゼを極めて低濃度で選択的に阻害する旨の報告（非特許文献５）などがある。 In addition, it was reported that the coexistence of tea catechin (EGCg) suppressed the absorption of cholesterol to the small intestinal mucosa in a concentration-dependent manner (Non-Patent Document 3), and that EGCg and ECg reduced the solubility of cholesterol in mixed micelles. Reports that this causes the suppression of cholesterol absorption from the intestinal tract (Non-Patent Document 4). Furthermore, EGCg and ECg reduce squalene epoxidase, one of the rate-limiting enzymes of cholesterol biosynthesis, at an extremely low concentration. There is a report of selective inhibition (Non-Patent Document 5).
さらにまた、茶カテキンがコレステロールの吸収を低下させることを動物と胆汁酸ミセルのモデルを使って証明したことに関し、この効果はＥＧＣｇ及びＥＣｇの方がＥＧＣ及びＥＣよりもはるかに高く、ガロイル基の存在によってできた疎水領域がコレステロールと相互作用して優れたコレステロール吸収低下作用を発揮することを示唆していると考察している記載も見られる（非特許文献６）。
本発明は、カテキンの血清コレステロール降下作用について更に研究を進め、その結果得られた新たな知見に基づいて、本発明の血清コレステロール低下剤及び血清コレステロール低下飲食物を提供せんとするものである。 The present invention is intended to provide a serum cholesterol-lowering agent and a serum cholesterol-lowering food and drink according to the present invention based on new findings obtained by further studying the serum cholesterol-lowering effect of catechin.
本発明者が、（−）エピカテキン(ＥＣ)、（−）エピガロカテキン(ＥＧＣ)、（−）エピカテキンガレート(ＥＣｇ)及び（−）エピガロカテキンガレート(ＥＧＣｇ)、（−）カテキン(Ｃ)、（−）ガロカテキン(ＧＣ)、（−）カテキンガレート(Ｃｇ)及び（−）ガロカテキンガレート(ＧＣｇ)の８種類の全カテキンについて血清コレステロール降下作用試験を行った結果、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇに優れた血清コレステロール降下作用を見出した。中でも非エピ体である（−）Ｃｇ及び（−）ＧＣｇは、エピ体である（−）ＥＣｇ及び（−）ＥＧＣｇよりも、一層優れた血清コレステロール降下作用を示すという新知見を見出し、かかる知見に基づいて本発明を想到した。 The present inventors have proposed that (-) epicatechin (EC), (-) epigallocatechin (EGC), (-) epicatechin gallate (ECg) and (-) epigallocatechin gallate (EGCg), (-) catechin ( (C), (-) gallocatechin (GC), (-) catechin gallate (Cg), and (-) gallocatechin gallate (GCg), all eight catechins were subjected to serum cholesterol-lowering effect test. (−) EGCg, (−) ECg, (−) GCg and (−) Cg, which were excellent in serum cholesterol lowering action. Among them, a new finding that (−) Cg and (−) GCg, which are non-epi isomers, show more excellent serum cholesterol lowering action than (−) ECg and (−) EGCg, which are epi isomers, was found. The present invention has been made based on the above.
本発明は、（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を有効成分とする血清コレステロール低下剤及び血清コレステロール低下効果を備えた飲食物（本発明では食品及び飲料をまとめて「飲食物」という。よって、飲食物には食品及び飲料が含まれる。）を提案する。 The present invention relates to a serum cholesterol-lowering agent comprising (-) GCg, (-) Cg or a mixture thereof as an active ingredient, and a food or drink having a serum cholesterol-lowering effect (in the present invention, foods and beverages are collectively referred to as "food and drink"). Therefore, foods and beverages include foods and beverages.).
（−）ＧＣｇ及び（−）Ｃｇは、それぞれ（−）ＥＧＣｇ及び（−）ＥＣｇのエピマー、すなわち（−）ＥＧＣｇ及び（−）ＥＣｇの一つの不斉炭素原子が反転した立体配置を持つジアステレオマー（鏡像異性体以外のすべての立体異性体）である。これら（−）ＧＣｇ及び（−）Ｃｇは、天然物（例えば茶葉）中に僅かに含まれるのみであるが、天然物（例えば茶葉）中に多く含まれている（−）ＥＧＣｇや（−）ＥＣｇを熱異性化することによって産業上利用できる程度に得ることができる。 (−) GCg and (−) Cg are epimers of (−) EGCg and (−) ECg, that is, diastereomers having a configuration in which one asymmetric carbon atom of (−) EGCg and (−) ECg is inverted. (All stereoisomers other than enantiomers). These (−) GCg and (−) Cg are only slightly contained in natural products (for example, tea leaves), but are often contained in natural products (for example, tea leaves) in large amounts (−) EGCg and (−). ECg can be obtained to a degree industrially usable by thermal isomerization.
従来、非エピ体である（−）ＧＣｇ及び（−）Ｃｇの薬理活性、特に血清コレステロール降下作用について考察した報告はほとんどみられなかったが、本発明者は、血清コレステロールの低下作用、詳しくは血清総コレステロール及び血清ＬＤＬ−コレステロールの低下作用に関して、非エピ体である（−）Ｃｇ及び（−）ＧＣｇが、エピ体である（−）ＥＣｇや（−）ＥＧＣｇなどよりも優れた効果を発揮することを見出し、これら（−）ＧＣｇ及び（−）Ｃｇを血清コレステロール低下剤或いはコレステロール低下飲食物の有効成分とすることで、従来よりもより一層薬理効果の優れた血清コレステロール低下剤及び飲食物を得ることができた。 Heretofore, there have been few reports on the pharmacological activity of non-epi (−) GCg and (−) Cg, especially the serum cholesterol lowering effect. However, the present inventors have found that the serum cholesterol lowering effect, With respect to the serum total cholesterol and serum LDL-cholesterol lowering effects, non-epitopic (-) Cg and (-) GCg exert superior effects than epi-(-) ECg and (-) EGCg, etc. By using these (-) GCg and (-) Cg as serum cholesterol-lowering agents or active ingredients of cholesterol-lowering foods and drinks, serum-cholesterol-lowering agents and foods and drinks having more excellent pharmacological effects than before can be obtained. Could be obtained.
本発明はまた、血清コレステロール低下剤の製造方法として、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを合計で約５００ｍｇ／Ｌ以上含有するカテキン溶液を作製し、これを約８０℃以上で加熱処理した後濃縮・乾燥することを特徴とする製造方法を提案する。
また、血清コレステロール低下効果を備えた飲食物の製造方法として、エステル型カテキン類（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを合計で約５００ｍｇ／Ｌ以上含有するカテキン溶液を作製し、これを約８０℃以上で加熱処理後濃縮・乾燥し、得られた濃縮乾燥物を配合することを特徴とする製造方法を提案する。
また、血清コレステロール低下効果を備えた飲料の製造方法として、エステル型カテキン類（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを合計で約５００〜６０００ｍｇ／Ｌ含有するカテキン溶液を作製し、これを約８０℃以上で加熱処理することを特徴とする製造方法を提案する。
いずれの製造方法も、エステル型カテキン類を所定値以上含有するカテキン溶液を作製し、これを加熱処理することによって（−）ＥＧＣｇ及び（−）ＥＣｇの熱異性化を促して（−）ＧＣｇ及び（−）Ｃｇの含有量を高めることができる特徴を備えている。
The present invention also provides a method for producing a serum cholesterol-lowering agent, comprising a catechin containing ester-type catechins (−) EGCg, (−) ECg, (−) GCg and (−) Cg in a total amount of about 500 mg / L or more. A manufacturing method is proposed in which a solution is prepared, heat-treated at about 80 ° C. or higher, and then concentrated and dried.
As a method for producing a food or drink having a serum cholesterol lowering effect, a catechin containing ester-type catechins (−) EGCg, (−) ECg, (−) GCg and (−) Cg in a total amount of about 500 mg / L or more. A manufacturing method is proposed in which a solution is prepared, heat-treated at about 80 ° C. or higher, concentrated and dried, and the obtained concentrated and dried product is blended.
As a method for producing a beverage having a serum cholesterol-lowering effect, a catechin containing ester-type catechins (−) EGCg, (−) ECg, (−) GCg and (−) Cg in a total amount of about 500 to 6000 mg / L. A manufacturing method is proposed in which a solution is prepared and heated at about 80 ° C. or higher.
In any of the production methods, a catechin solution containing an ester-type catechin or the like at a predetermined value or more is prepared and heat-treated to promote the thermal isomerization of (−) EGCg and (−) ECg, thereby promoting (−) GCg and (-) It has a feature that the content of Cg can be increased.
なお、本発明において「全カテキン」とは、（−）ＥＣ、（−）ＥＧＣ、（−）ＥＣｇ及び（−）ＥＧＣｇ、（−）Ｃ、（−）ＧＣ、（−）Ｃｇ及び（−）ＧＣｇの８種類のカテキンの意であり、「エステル型カテキン類」とは（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇの４種類のカテキンの意である。また、「エピ体」とは（−）ＥＣ、（−）ＥＧＣ、（−）ＥＣｇ及び（−）ＥＧＣｇを意味し、「非エピ体」とは（−）Ｃ、（−）ＧＣ、（−）Ｃｇ及び（−）ＧＣｇを意味する。 In the present invention, “all catechins” mean (−) EC, (−) EGC, (−) ECg and (−) EGCg, (−) C, (−) GC, (−) Cg and (−). GCg means eight kinds of catechins, and “ester type catechins” means four kinds of catechins of (−) EGCg, (−) ECg, (−) GCg and (−) Cg. The “epi form” means (−) EC, (−) EGC, (−) ECg and (−) EGCg, and the “non-epi form” means (−) C, (−) GC, (−) ) Means Cg and (-) GCg.
「（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を有効成分とする」の「有効成分とする」とは、（−）ＧＣｇ又は（−）Ｃｇの血清コレステロール低下作用が阻害されなければ、その他の成分、例えば（−）ＥＣ、（−）ＥＣｇ、（−）ＥＧＣｇなどの成分を含んでいてもよいという意を包含する。
また、（−）ＧＣｇの重合体、（−）ＧＣｇと他のカテキンとの共重合体、（−）Ｃｇの重合体、或いは（−）Ｃｇと他のカテキンとの共重合体は、「（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物」の均等物であると考えることができる。
The term “the active ingredient” of “the active ingredient of (−) GCg, (−) Cg or a mixture thereof” means that the serum cholesterol lowering action of (−) GCg or (−) Cg is not inhibited. It includes the meaning that other components such as (-) EC, (-) ECg, (-) EGCg and the like may be contained.
Further, a polymer of (−) GCg, a copolymer of (−) GCg and another catechin, a polymer of (−) Cg, or a copolymer of (−) Cg and another catechin is “( −) GCg, (−) Cg or a mixture thereof ”.
次に本発明の実施の形態について説明する。 Next, an embodiment of the present invention will be described.
（血清コレステロール低下剤）
本発明の血清コレステロール低下剤は、（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を所望濃度で配合することによって製造することができる。但し、（−）ＧＣｇ及び（−）Ｃｇの薬理活性を阻害しない範囲でその他の成分を配合したり、その他の処理を施すことは適宜可能である。
(Serum cholesterol lowering agent)
The serum cholesterol lowering agent of the present invention can be produced by blending (-) GCg, (-) Cg or a mixture thereof at a desired concentration. However, it is possible to appropriately mix other components or perform other treatments as long as the pharmacological activity of (−) GCg and (−) Cg is not inhibited.
（−）ＧＣｇ及び（−）Ｃｇは、従来公知の方法或いは今後公知となる方法によって得ることができる。
（−）ＧＣｇ及び（−）Ｃｇは、茶葉を含めて天然植物中にほとんど存在しないが、例えば「（−）ＥＧＣｇ、（−）ＥＣｇ或いはこれらの混合物」を約８０℃以上で加熱処理して熱異性化（エピマ−化）を促すことにより得ることができる。
よって、「（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物」は、例えば精製した（−）ＥＧＣｇ或いは（−）ＥＣｇ或いはこれらの混合物、又は、茶の抽出液或いは浸出液などの「（−）ＥＧＣｇ及び（−）ＥＣｇを含有するカテキン溶液」を、約８０℃以上で加熱処理してカテキンの熱異性化を促すことにより（−）ＧＣｇ又は（−）Ｃｇの含有濃度を高めることができ、この加熱処理物から（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物、或いはこれらを高濃度で含有する混合物を分離・精製することにより得ることができる。
この際、カテキン溶液をｐＨ５〜６に調製した上で加熱処理するのが好ましい。ｐＨ４．５以下ではカテキンはほとんど熱異性化しない可能性がある（末松伸一ら、：日食工誌、39,178(1992)）。
(−) GCg and (−) Cg can be obtained by a conventionally known method or a method known in the future.
Although (-) GCg and (-) Cg hardly exist in natural plants including tea leaves, for example, "(-) EGCg, (-) ECg or a mixture thereof" is heat-treated at about 80 ° C. or more. It can be obtained by promoting thermal isomerization (epimerization).
Therefore, “(−) GCg, (−) Cg or a mixture thereof” is, for example, “(−)” such as purified (−) EGCg or (−) ECg or a mixture thereof, or a tea extract or infusion. A catechin solution containing EGCg and (−) ECg ”is heated at about 80 ° C. or higher to promote thermal isomerization of catechin, thereby increasing the content of (−) GCg or (−) Cg, It can be obtained by separating and purifying (-) GCg, (-) Cg or a mixture thereof, or a mixture containing these at a high concentration from the heat-treated product.
At this time, it is preferable to heat the catechin solution after adjusting the pH to 5 to 6. There is a possibility that catechin hardly undergoes thermal isomerization at a pH of 4.5 or less (Shinmatsu Suematsu et al .: Nisshoku Kogaku, 39,178 (1992)).
上記の「（−）ＥＧＣｇ及び（−）ＥＣｇを含有するカテキン溶液」の組成としては、エステル型カテキン類を合計で約５００ｍｇ／Ｌ以上含有するように調製するのが好ましい。
また、上記の分離・精製方法は、従来公知の方法或いは今後公知となる方法を採用することができる。一例を挙げれば、被処理液（例えば茶の抽出液）を例えば水−アセトニトリル−リン酸の混合液を移動相とした逆相ＨＰＬＣにかけ、アセトニトリル濃度でグラジエントをかけることによって（−）ＧＣｇ及び（−）Ｃｇをそれぞれ分離することができる。
The composition of the “catechin solution containing (−) ECCg and (−) ECg” is preferably prepared so as to contain ester-type catechins in a total amount of about 500 mg / L or more.
Further, as the above separation / purification method, a conventionally known method or a method known in the future can be adopted. As an example, the liquid to be treated (eg, a tea extract) is subjected to, for example, reverse-phase HPLC using a mixed solution of water-acetonitrile-phosphoric acid as a mobile phase, and a gradient is applied at an acetonitrile concentration to obtain (−) GCg and ( -) Each Cg can be separated.
「（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物」は、それぞれ単独で本発明の有効成分として配合することが可能であるが、既に或いは将来的に血清コレステロール低下作用が認められた物質、例えば（−）ＥＣ、（−）ＥＣｇ、（−）ＥＧＣｇのいずれか或いはこれら二種類以上の組合せからなる混合物などと混合し、これらを有効成分とすることも可能である。
単独で本発明の有効成分として配合する場合、例えば（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を、精製水や生理食塩水などに溶解して血清コレステロール低下剤（例えば経口投与剤、腹腔内投与剤等）とすることもできる。
"(-) GCg, (-) Cg or a mixture thereof" can be used alone as the active ingredient of the present invention. For example, (-) EC, (-) ECg, (-) EGCg, or a mixture of a combination of two or more of these may be used as an active ingredient.
When formulated alone as the active ingredient of the present invention, for example, (-) GCg, (-) Cg or a mixture thereof is dissolved in purified water, physiological saline, or the like, and a serum cholesterol lowering agent (for example, an oral administration agent, peritoneal cavity) And the like).
本発明の血清コレステロール低下剤は、経口投与剤または非経口投与剤（筋肉注射、静脈注射、皮下投与、直腸投与、経皮投与、経鼻投与など）として使用することができ、それぞれの投与に適した配合及び剤型とするのが好ましい。
剤型について言えば、例えば経口投与剤用としては液剤、錠剤、散剤、顆粒、糖衣錠、カプセル、懸濁液、乳剤、丸剤などの形態に調製することができ、非経口投与剤用としては注射剤、アンプル剤、直腸投与剤、油脂性坐剤、水溶性坐剤などの形態に調製することができる。
配合（製剤）について言えば、通常用いられている賦形剤、増量剤、結合剤、湿潤化剤、崩壊剤、表面活性剤、潤滑剤、分散剤、緩衝剤、保存剤、溶解補助剤、防腐剤、矯味矯臭剤、無痛化剤、安定化剤などを用いて常法により製造することができる。また、例えば乳糖、果糖、ブドウ糖、でん粉、ゼラチン、炭酸マグネシウム、合成ケイ酸マグネシウム、タルク、ステアリン酸マグネシウム、メチルセルロース、カルボキシメチルセルロースまたはその塩、アラビアゴム、ポリエチレングリコール、シロップ、ワセリン、グリセリン、エタノール、プロピレングリコール、クエン酸、塩化ナトリウム、亜硫酸ソーダ、リン酸ナトリウムなどの無毒性の添加剤を配合することも可能である。
The serum cholesterol-lowering agent of the present invention can be used as an oral or parenteral agent (intramuscular injection, intravenous injection, subcutaneous administration, rectal administration, transdermal administration, nasal administration, etc.). It is preferred to have a suitable formulation and dosage form.
With respect to the dosage form, for example, for oral administration, it can be prepared in the form of liquid, tablet, powder, granule, dragee, capsule, suspension, emulsion, pill, etc., and for parenteral administration. It can be prepared in the form of injection, ampoule, rectal administration, oily suppository, water-soluble suppository and the like.
As for the formulation (formulation), commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, dissolution aids, It can be produced by a conventional method using a preservative, a flavoring agent, a soothing agent, a stabilizer and the like. Also, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, propylene It is also possible to incorporate non-toxic additives such as glycol, citric acid, sodium chloride, sodium sulfite, and sodium phosphate.
本発明の血清コレステロール低下剤は、医薬品のほか、医薬部外品、薬理効果を備えた健康食品・健康飲料・特定保健用食品・機能性食品、食品添加剤、その他ヒト以外の動物に対する薬剤や餌、餌用添加剤などとして提供することもできる。
例えば、医薬部外品として調製し、これを瓶ドリンク飲料等の飲用形態、或いはタブレット、カプセル、顆粒等の形態とすることにより、より一層摂取し易くすることができる。
Serum cholesterol lowering agent of the present invention, in addition to pharmaceuticals, quasi-drugs, health foods and health drinks with pharmacological effects, foods for specified health use, functional foods, food additives, other non-human animal drugs and They can also be provided as baits, bait additives and the like.
For example, by preparing it as a quasi-drug and making it into a drinking form such as a bottled drink or a form such as tablets, capsules, granules, etc., it is possible to make it easier to ingest.
血清コレステロール低下効果を備えた健康食品・健康飲料・特定保健用食品・機能性食品としては、例えば、（−）ＧＣｇ、（−）Ｃｇ、或いはこれらの混合物、或いはこの混合物を含むカテキン溶液を、炭酸、賦形剤（造粒剤含む）、希釈剤、或いは更に甘味剤、フレーバー、小麦粉、でんぷん、糖、油脂類等の各種タンパク質、糖質原料やビタミン、ミネラルなどの飲食品材料群から選ばれた一種或いは二種以上と混合したり、或いは、現在公知の飲食品、例えばスポーツ飲料、果実飲料、乳飲料、茶飲料、野菜ジュース、乳性飲料、アルコール飲料、ゼリー、ゼリー飲料、炭酸飲料、チューインガム、チョコレート、キャンディ、ビスケット、スナック、パン、乳製品、魚肉練り製品、畜肉製品、冷菓、乾燥食品、サプリメントなどに添加して製造することができる。
中でも、脂肪を多く含んだ飲食物に（−）ＧＣｇ、（−）Ｃｇ、或いはこれらの混合物、或いはこの混合物を含むカテキン溶液などを加えて飲食物を調製すれば、含有脂肪の割にコレステロールの上昇を抑制することができるから、低コレステロール飲食物或いはダイエット飲食物などとして提供することができる。
Examples of health foods, health drinks, foods for specified health use, and functional foods having a serum cholesterol lowering effect include (-) GCg, (-) Cg, or a mixture thereof, or a catechin solution containing the mixture. Carbonate, excipients (including granules), diluents, or even sweeteners, flavors, flour, starch, sugar, fats and other proteins, and food and drink materials such as carbohydrate raw materials, vitamins, and minerals Mixed with one or more of the above, or currently known foods and drinks such as sports drinks, fruit drinks, milk drinks, tea drinks, vegetable juices, milk drinks, alcoholic drinks, jelly, jelly drinks, carbonated drinks , Chewing gum, chocolate, candy, biscuits, snacks, bread, dairy products, fish paste products, animal meat products, frozen desserts, dried foods, supplements, etc. It can be produced by pressing.
Above all, if a food or drink is prepared by adding (-) GCg, (-) Cg, or a mixture thereof, or a catechin solution containing the mixture to a food or drink containing a large amount of fat, cholesterol is contained in addition to the fat contained. Since the rise can be suppressed, it can be provided as a low cholesterol food or drink or a diet food or drink.
（血清コレステロール低下飲食物）
次に、本発明の血清コレステロール低下効果を備えた飲食物（すなわち、血清コレステロール低下食品及び飲料を含む。）、中でも茶由来の血清コレステロール低下飲料について詳しく説明する。
(Food and drink that lowers serum cholesterol)
Next, the foods and drinks having a serum cholesterol-lowering effect of the present invention (that is, foods and beverages including serum cholesterol-lowering foods), particularly tea-derived serum cholesterol-lowering beverages, will be described in detail.
上述のように、（−）ＧＣｇ及び（−）Ｃｇは、天然の茶中にほとんど存在しないが、天然の茶に多く含まれている（−）ＥＧＣｇ、（−）ＥＣｇ或いはこれらの混合物を加熱処理することにより得ることができる。
よって、（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを所定量以上含有する（これら以外を含んでいてもよい。）カテキン溶液を作製し、これを加熱処理することにより（−）ＧＣｇ及び（−）Ｃｇを所望量含有する茶由来の血清コレステロール低下飲料を製造することができる。
例えば、茶を抽出して得られる茶抽出物（（−）ＥＧＣｇ及び（−）ＥＣｇ含有）を、水等に加えて（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを所定量以上含有する（これら以外を含んでいてもよい。）カテキン溶液を作製し、これを加熱処理することにより（−）ＧＣｇ及び（−）Ｃｇを所望量含有する所望組成の茶由来の血清コレステロール低下飲料を製造することができる。
As described above, (-) GCg and (-) Cg hardly exist in natural tea, but (-) EGCg, (-) ECg, or a mixture thereof, which is abundantly contained in natural tea, is heated. It can be obtained by processing.
Accordingly, a catechin solution containing (-) EGCg, (-) ECg, (-) GCg, and (-) Cg in a predetermined amount or more (may contain other than these) is prepared and heat-treated. As a result, a tea-derived serum cholesterol-lowering beverage containing desired amounts of (-) GCg and (-) Cg can be produced.
For example, a tea extract (containing (−) EGCg and (−) ECg) obtained by extracting tea is added to water or the like, and (−) EGCg, (−) ECg, (−) GCg, and (−) Cg are added. A catechin solution containing a predetermined amount or more (may contain other than these) may be prepared and heat-treated to prepare a catechin solution derived from tea having a desired composition containing desired amounts of (−) GCg and (−) Cg. A serum cholesterol-lowering beverage can be manufactured.
この際、原料とし得る茶は、（−）ＥＧＣｇ及び（−）ＥＣｇを含有していれば特に種類、部位などには制限されないが、例えば茶生葉、紅茶やプアール茶等の発酵茶、ウーロン茶や包種茶等の半発酵茶、緑茶や釜煎り緑茶、ほうじ茶等の不発酵茶のいずれか（単独）、又は、これらの２種類以上の混合物を抽出して得られるもの、或いはそれぞれを抽出して得られたものの混合物を用いることができる。 At this time, the type of tea, which can be used as a raw material, is not particularly limited as long as it contains (−) EGCg and (−) ECg, but, for example, fresh tea leaves, fermented tea such as black tea and Poual tea, oolong tea, Either semi-fermented tea such as wrapped tea, unfermented tea such as green tea, pot roasted green tea, or roasted tea, or a mixture obtained by extracting a mixture of two or more of these, or extracting each A mixture of those obtained by the above method can be used.
茶の抽出は、茶を水、温水または熱水、好ましくは４０℃〜１００℃の温熱水、中でも９０〜１００℃の熱水、或いは人体に無害なエタノール水溶液またはエタノールなどの有機溶媒で抽出して茶抽出物を得ればよい。更にこの茶抽出物を溶媒抽出法、樹脂吸着法、限外濾過・逆浸透濾過等の濾過などの精製手段によってカテキン、中でも（−）ＥＧＣ及び（−）ＥＣｇの含有量を高める方向に精製して茶抽出物を得ることもできる。抽出の際、（−）ＥＧＣ及び（−）ＥＣｇの含有量を高めるべく塩酸等を添加して酸性条件下で抽出を行ってもよい。 Extraction of tea is performed by extracting tea with water, hot water or hot water, preferably hot water at 40 ° C to 100 ° C, especially hot water at 90 to 100 ° C, or an organic solvent such as an aqueous ethanol solution or ethanol harmless to the human body. Tea extract. Further, this tea extract is purified by a purification method such as solvent extraction, resin adsorption, filtration such as ultrafiltration / reverse osmosis filtration, in such a manner as to increase the content of catechin, especially (−) EGC and (−) ECg. Tea extract can also be obtained. At the time of extraction, hydrochloric acid or the like may be added to increase the content of (−) EGC and (−) ECg, and extraction may be performed under acidic conditions.
また、市販の茶抽出物を用いることがもできる。例えば、テアフラン３０Ａ（商品名；伊藤園社製）は、緑茶を熱水抽出処理し、この抽出物を乾燥させてカテキン濃度を約３０％とした緑茶抽出物であり、テアフラン９０Ｓ（商品名；伊藤園社製）は、緑茶を熱水抽出処理して得た抽出物を、水と低・高濃度アルコールを使って吸着カラムにて分離し乾燥させ、茶ポリフェノール濃度を約８５〜９９．５％とした緑茶抽出物である。その他、市販の茶抽出物として三井農林（株）製「ポリフェノン」、太陽化学（株）製「サンフェノン」、サントリー（株）製「サンウーロン」等も用いることができる。 Also, a commercially available tea extract can be used. For example, Theafuran 30A (trade name; manufactured by ITO EN Co., Ltd.) is a green tea extract obtained by subjecting green tea to hot water extraction treatment and drying the extract to have a catechin concentration of about 30%. ) Is separated from the extract obtained by hot water extraction of green tea with an adsorption column using water and low-concentration and high-concentration alcohols and dried, and the tea polyphenol concentration is about 85 to 99.5%. Green tea extract. In addition, as a commercially available tea extract, "Polyphenon" manufactured by Mitsui Norin Co., Ltd., "Sunphenon" manufactured by Taiyo Kagaku Co., Ltd., "Sunoolon" manufactured by Suntory Ltd., etc. can be used.
「カテキン溶液」の組成としては、エステル型カテキン類を合計で約５００ｍｇ／Ｌ以上含有するように調製するのが好ましい。カテキン溶液のエステル型カテキン類濃度が５００ｍｇ／Ｌ未満では、途中で濃縮工程が必要となるため生産コストが過大となる可能性がある。 The composition of the “catechin solution” is preferably prepared so as to contain ester-type catechins in a total amount of about 500 mg / L or more. If the concentration of the ester-type catechins in the catechin solution is less than 500 mg / L, a concentration step is required on the way, so that the production cost may be excessive.
カテキン溶液の加熱処理は、約８０℃以上で加熱処理するのが好ましい。試験結果を見ると、例えば１００℃×１５分加熱、１１５℃×２０分加熱、１２０℃×３〜３０分加熱、１２３℃×１０分加熱、１３１℃×３０秒加熱、１３３℃×４５秒のいずれにおいても、カテキン類の熱異性化が認められている。
カテキン溶液の加熱処理が８０℃未満では、エステル型カテキン類のエピ体から非エピ体への変換（熱異性化）が容易に起こらず、また平衡がエピ体リッチの方向にシフトするため好ましくない。
また、好ましくはカテキン溶液をｐＨ５〜６に調製した上で加熱処理するのが好ましい。ｐＨ４．５以下ではカテキン類はほとんど熱異性化しないという旨の報告もある（末松伸一ら、：日食工誌、39,178(1992)）。
The heat treatment of the catechin solution is preferably performed at about 80 ° C. or higher. Looking at the test results, for example, heating at 100 ° C. × 15 minutes, heating at 115 ° C. × 20 minutes, heating at 120 ° C. × 3 to 30 minutes, heating at 123 ° C. × 10 minutes, heating at 131 ° C. × 30 seconds, and heating at 133 ° C. × 45 seconds In all cases, thermal isomerization of catechins has been observed.
When the heat treatment of the catechin solution is lower than 80 ° C., conversion of the ester-type catechins from an epi-isomer to a non-epi-isomer (thermal isomerization) does not easily occur, and the equilibrium is shifted in a direction rich in the epi-isomer. .
Preferably, the catechin solution is adjusted to pH 5 to 6 and then heat-treated. There is also a report that catechins hardly undergo thermal isomerization at pH 4.5 or lower (Shinmatsu Suematsu et al .: Nisshoku Kogaku, 39,178 (1992)).
本発明の血清コレステロール低下飲料は、上記のようにして得られたカテキン溶液の加熱処理液をそのまま或いは風味改善のため適宜緑茶抽出液やその他の物質を添加して調製すればよい。
ちなみに、本発明の血清コレステロール低下剤及び血清コレステロール低下飲食物は、上記のようにして得られたカテキン溶液の加熱処理液をさらに濃縮・乾燥し、得られた固形物を配合して製造することができる。この際の濃縮・乾燥工程は、減圧濃縮や凍結乾燥など通常の濃縮・乾燥方法により行うことができる。
The serum cholesterol-lowering beverage of the present invention may be prepared by using the heat-treated solution of the catechin solution obtained as described above as it is or by appropriately adding a green tea extract and other substances for improving the flavor.
Incidentally, the serum cholesterol-lowering agent and the serum cholesterol-lowering food and drink of the present invention are produced by further concentrating and drying the heat-treated solution of the catechin solution obtained as described above, and blending the obtained solid. Can be. The concentration / drying step at this time can be performed by a usual concentration / drying method such as concentration under reduced pressure or freeze drying.
このようにして得られた血清コレステロール低下飲食物は、主原料が、天然物、特に日常多量に引用している茶から得た成分を用いるので、安心して日常的に飲むことができる保健飲料として提供することができる。 Serum cholesterol-lowering foods obtained in this way are mainly used as health drinks that can be safely and routinely used because the main ingredients are natural products, especially ingredients obtained from tea, which are cited in large quantities daily. Can be provided.
次に、本発明の血清コレステロール低下飲食物の好ましい配合組成について説明する。 Next, a preferred composition of the serum cholesterol-lowering food and drink of the present invention will be described.
本発明の血清コレステロール低下飲食物は、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを合計で、全カテキン合計含有量の約７０重量％以上含有し、かつ、次の（１）〜（３）の条件を満足するのが好ましい。
（１）（−）ＧＣｇ及び（−）Ｃｇの合計含有量が、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇの合計含有量の約４０重量％以上である。
（２）（−）ＥＣｇの含有量が、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇの合計含有量の約２０重量％以下である。
（３）（−）ＧＣｇの含有量が、（−）ＥＣｇの含有量以上である。
The serum cholesterol-lowering food and drink of the present invention comprises ester-type catechins (-) EGCg, (-) ECg, (-) GCg and (-) Cg in a total amount of about 70% by weight or more of the total content of all catechins. It is preferable that it is contained and satisfies the following conditions (1) to (3).
(1) The total content of (−) GCg and (−) Cg is about 40 of the total content of (−) EGCg, (−) ECg, (−) GCg and (−) Cg which are ester catechins. % By weight or more.
(2) The content of (-) ECg is about 20% by weight or less of the total content of (-) EGCg, (-) ECg, (-) GCg, and (-) Cg, which are ester-type catechins.
(3) The content of (-) GCg is not less than the content of (-) ECg.
後述するように、本発明者の検討の結果、４種類のエステル型カテキンに血清コレステロール低下作用があることが明らかになったが、エステル型カテキン類のみで血清コレステロール低下飲食物中のカテキンを構成しようとすると、風味が不足するため摂取しにくいものとなる。そこで、緑茶抽出物を添加して飲食物中の（−）ＥＣの濃度を指標としてその値を、市販の緑茶飲料の２倍程度までの値とすることにより摂取の困難さを改善しようとすると、緑茶抽出物の必要添加量は最大当該飲食物の全カテキン含有量と等量程度となり、この場合の本発明の血清コレステロール低下飲食物中の４種類のエステル型カテキン類の合計含有量は、８種類の全カテキンの合計含有量の約７０重量％以上となる。エステル型カテキン類の含有割合は変化させて呈味試験を行ったところ、全カテキンの合計含有量の約７０重量％以上となるように飲料を調製するのが呈味性の上では好ましいことが確認された。 さらに、エステル型カテキン類の満足すべき条件（１）〜（３）に関して言えば、（１）については、非エピ体の血清コレステロール低減効果がエピ体（それなりに効果がある）のそれより優れているため、非エピ体、特に（−）ＧＣｇ及び（−）Ｃｇの合計含有量が、エピ体を含めたエステル型カテキン類の合計含有量の少なくとも約４０重量％を占めるのが好ましいからである。（２）については、ＥＣｇの血清コレステロール低減効果がエステル型カテキン中もっとも小さいため、（−）ＥＣｇの含有量が、エステル型カテキン類の合計含有量の約２０重量％以下とするのが好ましいからである。（３）については、ＥＣｇの低減効果の低さを、最も低減効果の優れているＧＣｇで補償するため、（−）ＧＣｇの含有量を（−）ＥＣｇの含有量以上とするのが好ましいからである。
以上の条件を満たす本発明の血清コレステロール低下飲食物は、そのエステル型カテキンの合計量と同量のＥＧＣｇを含有する飲食物と同等若しくはそれ以上の血清コレステロール低下作用を発揮する。
As will be described later, as a result of the study by the present inventors, it has been revealed that four types of ester-type catechins have a serum cholesterol-lowering effect, but only ester-type catechins constitute catechins in serum cholesterol-lowering foods. Attempting to do so would make it difficult to ingest due to lack of flavor. Therefore, it is desired to improve the difficulty of ingestion by adding a green tea extract and setting the value of the concentration of (-) EC in food and drink as an index up to about twice that of a commercially available green tea beverage. The required addition amount of the green tea extract is about the same as the total catechin content of the food or drink at the maximum, and in this case, the total content of the four ester-type catechins in the serum cholesterol-lowering food and drink of the present invention is: This is about 70% by weight or more of the total content of all eight catechins. A taste test was conducted by changing the content of the ester-type catechins, and it was found that it is preferable in terms of taste to prepare a beverage so as to be about 70% by weight or more of the total content of all catechins. confirmed. Furthermore, regarding the satisfactory conditions (1) to (3) of the ester-type catechins, in the case of (1), the serum cholesterol lowering effect of the non-epi form is superior to that of the epi form (somewhat effective). Therefore, it is preferable that the total content of non-epi isomers, particularly (-) GCg and (-) Cg, accounts for at least about 40% by weight of the total content of ester-type catechins including epi-isomer. is there. Regarding (2), since the serum cholesterol lowering effect of ECg is the smallest among ester-type catechins, the content of (−) ECg is preferably set to about 20% by weight or less of the total content of ester-type catechins. It is. Regarding (3), the content of (−) GCg is preferably set to be equal to or more than the content of (−) ECg in order to compensate for the low ECg reduction effect with the GCg having the best reduction effect. It is.
The serum cholesterol-lowering food and drink of the present invention that satisfies the above conditions exhibits a serum cholesterol lowering effect equal to or higher than that of food and drink containing the same amount of EGCg as the total amount of the ester-type catechin.
（必要摂取量及び含有量）
本発明の血清コレステロール低下剤及び血清コレステロール低下飲食物におけるエステル型カテキン類の必要摂取量は、１日当たり約３００〜２１００ｍｇ程度であると考えられる。
使用方法によっても異なるが、（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を、乾燥重量換算で大人一日に１２０〜２１００ｍｇ、好ましくは２５０〜１５００ｍｇ程度摂取するのが好ましい。
(Necessary intake and content)
It is considered that the required intake of the ester-type catechins in the serum cholesterol-lowering agent and the serum cholesterol-lowering food and drink of the present invention is about 300 to 2100 mg per day.
Although it depends on the method of use, it is preferable that (-) GCg, (-) Cg or a mixture thereof is ingested in an amount of about 120 to 2100 mg, preferably about 250 to 1500 mg per day per adult in terms of dry weight.
上記の必要摂取量から考えると、固形形態の血清コレステロール低下剤及び血清コレステロール低下飲食物の場合、エステル型カテキン類を約０．１〜１００重量％含有させるようにするのが好ましく、中でも（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を、約０．０４〜１００重量％、特に約０．１〜４０重量％配合するのが好ましい。
エステル型カテキン類約０．１重量％未満では、摂取すべき固形物の量が１日当たり約２ｋｇを超えることがあるため好ましくない。
In view of the above-mentioned required intake, in the case of the solid form serum cholesterol lowering agent and the serum cholesterol lowering food and drink, it is preferable to contain the ester-type catechins in an amount of about 0.1 to 100% by weight. ) GCg, (-) Cg or a mixture thereof is preferably incorporated in an amount of about 0.04 to 100% by weight, particularly about 0.1 to 40% by weight.
Ester catechins of less than about 0.1% by weight are not preferred because the amount of solids to be consumed may exceed about 2 kg per day.
他方、飲料形態の血清コレステロール低下剤及び血清コレステロール低下飲食物の場合、エステル型カテキン類を約５００〜６０００ｍｇ／Ｌ程度の濃度で含有させるのが好ましく、加熱処理後の飲料は（−）ＧＣｇ、（−）Ｃｇ或いはこれらの混合物を約２００〜６０００ｍｇ／Ｌ、特に約３００〜３０００ｍｇ／Ｌ程度の濃度で含有させるのが好ましい。
エステル型カテキン類濃度が５００ｍｇ／Ｌ未満では、摂取すべき飲料の体積が１日当たり４Ｌを超えることがあるため好ましくない。６０００ｍｇ/Ｌを超えると、カテキン類が高濃度となり渋味が強すぎるため好ましくない。より好ましくは、エステル型カテキン類濃度７５０〜３７５０ｍｇ／Ｌ程度である。
On the other hand, in the case of a serum cholesterol-lowering agent and a serum cholesterol-lowering food or drink in the form of a beverage, it is preferable to contain ester-type catechins at a concentration of about 500 to 6000 mg / L, and the beverage after the heat treatment is (-) GCg, It is preferable to contain (-) Cg or a mixture thereof at a concentration of about 200 to 6000 mg / L, particularly about 300 to 3000 mg / L.
If the concentration of the ester-type catechins is less than 500 mg / L, the volume of the beverage to be consumed may exceed 4 L per day, which is not preferable. If it exceeds 6000 mg / L, the concentration of catechins becomes high and the astringency is too strong, which is not preferable. More preferably, the concentration of the ester-type catechins is about 750 to 3750 mg / L.
＜試験１＞
茶カテキン類のコレステロール吸収阻害能を測定し、異性化カテキン（非エピ体カテキン）のコレステロール吸収阻害能を比較検討した。
<Test 1>
The ability of tea catechins to inhibit cholesterol absorption was measured, and the ability of isomerized catechins (non-epitopic catechins) to inhibit cholesterol absorption was compared.
茶カテキンのうち、エステル型カテキンとして（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇ、遊離型カテキンとして（−）ＥＧＣ、（−）ＥＣ、（−）ＧＣ及び（−）Ｃの合計８種のカテキンを試料として以下の試験を行った。 Among tea catechins, (-) EGCg, (-) ECg, (-) GCg and (-) Cg as ester catechins, and (-) EGC, (-) EC, (-) GC and (-) as free catechins. The following tests were performed using a total of eight catechins C) as samples.
（試験方法）
１５ｍＭ リン酸緩衝液（ｐＨ６．８）に０．５ｍＭコレステロール、６．６ｍＭタウロコ−ル酸Ｎａ、０．６ｍＭ卵黄レシチン、１３２ｍＭ ＮａＣｌを添加し、超音波処理により胆汁酸混合ミセル（以下［胆汁酸ミセル］という）を調製した。
この胆汁酸ミセルをアルゴンガス封入し、３７℃で２４時間保持してミセルを安定化させた後、脱イオン水に溶解させて上記８種類のカテキンをそれぞれ最終濃度１０００μＭ或いは２０００μＭとなるようにミセルに添加し、１時間インキュベートした。この際、いくつかのカテキン添加群においてミセル溶液は白濁し、沈殿した。なお、カテキン無添加群には、脱イオン水のみを添加した。
インキュベート開始から１時間後、この溶液を２２０ｎｍのフィルターでろ過し、清澄なミセル溶液を得、この溶液中のコレステロール濃度を測定した。結果を、図１及び図２に示す。
(Test method)
0.5 mM cholesterol, 6.6 mM Na taurocholate, 0.6 mM egg yolk lecithin and 132 mM NaCl were added to a 15 mM phosphate buffer (pH 6.8), and bile acid mixed micelles (hereinafter referred to as [bile acid] Micelle]).
The bile acid micelles were sealed with argon gas, kept at 37 ° C. for 24 hours to stabilize the micelles, and then dissolved in deionized water to dissolve the eight catechins in a final concentration of 1000 μM or 2000 μM, respectively. And incubated for 1 hour. At this time, the micelle solution became cloudy and precipitated in some catechin-added groups. In addition, only the deionized water was added to the catechin-free group.
One hour after the start of the incubation, this solution was filtered through a 220 nm filter to obtain a clear micelle solution, and the cholesterol concentration in this solution was measured. The results are shown in FIG. 1 and FIG.
（結果）
図１を見ると、エステル型カテキンである（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇを胆汁酸ミセルへ添加したものは、ミセル中のコレステロール濃度が添加量依存的に減少した。その作用は、１０００μＭ添加では、（−）ＥＧＣｇ、（−）ＧＣｇ、（−）Ｃｇは、（−）ＥＣｇに比較して強い低下作用を示した（Ｐ＜０．０５）。
前者の３種のカテキンのうちでは、（−）ＧＣｇが最も低下作用が強く、（−）ＥＧＣｇに対して有意に低下（Ｐ＜０．０５）し、次いで（−）Ｃｇ、（−）ＥＧＣｇの順であった。
他方、図２を見ると、遊離型カテキンである（−）ＥＧＣ、（−）ＥＣ、（−）ＧＣ及び（−）Ｃｇは、胆汁酸ミセル中のコレステロール濃度をほとんど低下させなかった。
(result)
Referring to FIG. 1, in the case where (−) EGCg, (−) ECg, (−) GCg and (−) Cg, which are ester type catechins, were added to bile acid micelles, the cholesterol concentration in the micelles was dependent on the amount added. Decreased to. The effect of (−) EGCg, (−) GCg, and (−) Cg showed a stronger lowering effect than that of (−) ECg when 1000 μM was added (P <0.05).
Among the former three catechins, (−) GCg has the strongest effect of lowering, significantly lowers (P <0.05) than (−) EGCg, and then (−) Cg, (−) EGCg. It was in order.
On the other hand, looking at FIG. 2, the free catechins (−) EGC, (−) EC, (−) GC and (−) Cg hardly reduced the cholesterol concentration in the bile acid micelles.
（考察）
以上の結果、カテキンのガレートエステルはエピ体（ｅｐｉ体）だけでなく、非エピ体（異性体）も胆汁酸混合ミセル中のコレステロールを沈殿させ、ミセルから脱離させていることが明らかとなった。
さらに、非エピ体（異性体）である（−）ＧＣｇ及び（−）Ｃｇのコレステロール低下作用は、エピ体（ｅｐｉ体）である（−）ＥＧＣｇ及び（−）ＥＣｇよりもその作用が強いと考えることができる。
(Discussion)
From the above results, it is clear that the catechin gallate ester precipitates cholesterol in the bile acid-mixed micelle and removes it from the micelle not only in the epi form (epi form) but also in the non-epi form (isomer). Was.
Further, the cholesterol lowering effect of (−) GCg and (−) Cg, which are non-epi isomers (isomer), is stronger than that of (−) EGCg and (−) ECg which are epi isomers (epi isomer). You can think.
＜試験２＞
異性化非エピ体カテキン混合物による相乗効果を検討すべく、試験１と同じ方法を用いて、（−）ＧＣｇ及び（−）Ｃｇを含むエステル型カテキン混合物（実施例１の飲料）、これらを含まないエステル型カテキン混合物、ＥＧＣｇの三者のコレステロール吸収阻害効果を比較検討した（図３）。
<
Using the same method as in Test 1, an ester-type catechin mixture containing (-) GCg and (-) Cg (the beverage of Example 1) was examined using the same method as in Test 1 in order to examine the synergistic effect of the isomerized non-epimeric catechin mixture. The cholesterol absorption inhibitory effects of the three ester-type catechin mixtures and EGCg were compared (FIG. 3).
なお、（−）ＧＣｇ及び（−）Ｃｇを含むエステル型カテキン混合物として下記実施例１の飲料を用い、この実施例飲料から試験１同様に胆汁酸混合ミセルを調製した。
また、（−）ＧＣｇ及び（−）Ｃｇを含まないエステル型カテキン混合物としてテアフラン９０Ｓ（伊藤園製緑茶抽出物、組成は表１参照）を用い、この実施例飲料から試験１同様に胆汁酸混合ミセルを調製した。
The beverage of Example 1 below was used as an ester-type catechin mixture containing (-) GCg and (-) Cg, and bile acid-mixed micelles were prepared from this example beverage in the same manner as in Test 1.
In addition, bile acid-mixed micelles from this example beverage were used in the same manner as in Test 1 using theafran 90S (green tea extract manufactured by ITO EN, see Table 1 for composition) as an ester-type catechin mixture containing no (-) GCg and (-) Cg. Was prepared.
この結果、ＥＧＣｇに比べて、いずれのエステル型カテキンの混合物も高い活性を示すことが分かった。また、本試験結果では、（−）ＧＣｇ及び（−）Ｃｇを含むエステル型カテキン混合物と含まないエステル型カテキン混合物との間に大きな活性の差は認められなかった。
なお、平成１５年２月１０日に出願に添付した図３は、（−）ＧＣｇ及び（−）Ｃｇを含まないエステル型カテキン混合物の方が高い活性を示す結果となっていたが、出願後この図面は誤記であることが発覚したので正しい図３に差し替えたものである。
As a result, it was found that all the ester-type catechin mixtures exhibited higher activities than EGCg. In addition, in the present test results, no significant difference in activity was observed between the ester-type catechin mixture containing (-) GCg and (-) Cg and the ester-type catechin mixture not containing.
In addition, FIG. 3 attached to the application on February 10, 2003 shows that the ester-type catechin mixture containing no (-) GCg and (-) Cg shows higher activity. This drawing was replaced with the correct one in FIG. 3 because it was found to be incorrect.
＜試験３＞
テアフラン９０Ｓ（伊藤園製カテキンエキス、組成は表１参照）を１４５０ｍｇ／Ｌの濃度となるように６０℃の温水に溶解させ、３５℃に冷却後ビタミンＣを３００ｍｇ／Ｌ添加し、次いでサイクロデキストリンを１重量％、緑茶エキスを０．２重量％、重曹を約３００ｍｇ／Ｌを加え、蒸留水で最終的に１ｋｇに調製してカテキン溶液を得た。この際、１缶当たりポリフェノールは２５０ｍｇ含有していた。
このようにして得られたカテキン溶液を、９５℃に加熱した後、缶の場合には缶に充填して１２３℃・１０分間の加熱処理（レトルト殺菌）を行い、また、ＰＥＴボトルの場合には９５℃に加熱した後１３３．５℃・４５秒の加熱処理（ＵＨＴ殺菌）を行ってＰＥＴボトルに充填し、その後各工程におけるカテキン類の含有量を測定し、それぞれの含有量（ｍｇ／Ｌ）を表２に示し、カテキン類の異性化率（変化率％）を表３に示した。
<
Theafuran 90S (Catechin extract manufactured by ITO EN, see Table 1 for composition) was dissolved in warm water at 60 ° C. to a concentration of 1450 mg / L, cooled to 35 ° C., added with 300 mg / L of vitamin C, and then cyclodextrin was added. 1% by weight, 0.2% by weight of green tea extract and about 300 mg / L of sodium bicarbonate were added, and finally adjusted to 1 kg with distilled water to obtain a catechin solution. At this time, 250 mg of polyphenol was contained per can.
After heating the catechin solution thus obtained to 95 ° C., in the case of a can, it is filled in a can and subjected to heat treatment (retort sterilization) at 123 ° C. for 10 minutes, and in the case of a PET bottle, Is heated to 95 ° C., heat-treated at 133.5 ° C. for 45 seconds (sterilized by UHT), filled into PET bottles, and then the content of catechins in each step is measured. L) is shown in Table 2, and the isomerization rate (change rate%) of the catechins is shown in Table 3.
ここで、飲料中における（−）ＥＧＣｇ、（−）ＧＣｇ、（−）ＥＣｇ及び（−）Ｃｇのコレステロール低下作用に関する寄与率を求めると、試験１より、（−）ＥＧＣｇ、（−）ＧＣｇ、（−）ＥＣｇ及び（−）Ｃｇは１００μＭにおけるミセル中の残存コレステロール濃度がそれぞれ２７２、２４４、３３７、２６２であったから、沈殿させたコレステロールは初期値４２５μＭとの差をとって１５３、１８１、８８、１６３となり、１μＭ当たりのコレステロール沈殿能は１．５３、１．８１、０．８８、１．６３となる。
他方、本試験飲料１９０ｍＬ中に含まれるカテキン組成を、（−）ＥＧＣｇ：（−）ＧＣｇ：（−）ＥＣｇ：（−）Ｃｇ＝５１．３ｍｇ（５８９．５μＭ）：６２．７ｍｇ（７２０．５μＭ）：１９．０ｍｇ（２２６．２μＭ）：１７．０ｍｇ（２０２．４μＭ）とすると、上記の１μＭ当たりのコレステロール沈殿能より、本試験飲料１９０ｍＬ中に含まれるカテキンのコレステロール低下作用に関する寄与率は、
（−）ＥＧＣｇ：（−）ＧＣｇ：（−）ＥＣｇ：（−）Ｃｇ＝３３．０：４７．７：７．３：１２．０（％）と算出できた。
Here, when the contribution ratio of the (−) EGCg, (−) GCg, (−) ECg and (−) Cg in the beverage with respect to the cholesterol lowering effect was determined, from Test 1, it was found that (−) EGCg, (−) GCg, Since (-) ECg and (-) Cg had residual cholesterol concentrations in micelles at 100 μM of 272, 244, 337 and 262, respectively, the precipitated cholesterol differed from the initial value of 425 μM by 153, 181 and 88. , 163 and the cholesterol precipitation ability per 1 μM is 1.53, 1.81, 0.88, 1.63.
On the other hand, the composition of catechin contained in 190 mL of the test beverage was (-) EGCg: (-) GCg: (-) ECg: (-) Cg = 51.3 mg (589.5 µM): 62.7 mg (720.5 µM). ): 19.0 mg (226.2 μM): Assuming 17.0 mg (202.4 μM), the contribution rate of catechin contained in 190 mL of the test beverage to the cholesterol-lowering effect from the cholesterol precipitation ability per 1 μM is as follows:
(−) EGCg: (−) GCg: (−) ECg: (−) Cg = 33.0: 47.7: 7.3: 12.0 (%)
＜試験４：ヒト試験＞
１）対象者
本試験は、健常な生活を営む２０歳以上の男性のうち、血清総コレステロールが２００ｍｇ／ｄＬ以上２８０ｍｇ／ｄＬ以下の境界領域および軽度高血清コレステロール値にある被験者４２名を、試験に直接参加しない医師により抽出した。
対象者は病院での加療を受けていない者であることを条件とし、入院や通院による脂質降下剤や降圧剤等の薬剤の服用者、重篤な肝機能障害、腎障害、呼吸器障害、内分泌障害、心血管障害のある者は対象から除外した。
試験開始にあたっては、４２名の被験者をＡ群、Ｂ群、Ｃ群の3群にわけ、各群１４名とした。開始時の各群の血圧や総コレステロール値に差はなかった。
<Test 4: Human test>
1) Subjects The present study was conducted on 42 healthy subjects who were healthy and aged 20 years or older and whose serum total cholesterol was 200 mg / dL or more and 280 mg / dL or less in the boundary region and mildly high serum cholesterol level. Extracted by physicians who do not participate directly in
The subject must be a patient who has not been treated at the hospital, who has taken medications such as lipid-lowering drugs or antihypertensive drugs due to hospitalization or hospital visit, severe liver dysfunction, renal disorder, respiratory disorder, Individuals with endocrine and cardiovascular disorders were excluded from the study.
At the start of the test, 42 subjects were divided into three groups, Group A, Group B, and Group C, and each group had 14 subjects. There were no differences in blood pressure or total cholesterol levels in each group at the start.
２）試験飲料
本試験には、茶カテキンを１本当たり１５０ｍｇ(茶ポリフェノールとして２５０ｍｇ:（株）伊藤園製商品名テアフラン９０Ｓ)となるよう配合した飲料１９０ｇを用いた。試験飲料中の茶カテキン組成を表４に示す。
試験飲料には茶カテキンのほか、茶カテキンを含まない緑茶抽出液、サイクロデキストリン、ビタミンＣを加えた。
また、プラセボ飲料として茶カテキン以外同成分の飲料を用いた。
2) Test Beverage In this test, 190 g of a beverage containing 150 mg of tea catechin (250 mg as a tea polyphenol: trade name Tearfuran 90S, manufactured by Itoen Co., Ltd.) was used. Table 4 shows the tea catechin composition in the test beverage.
To the test beverage, tea catechin, green tea extract containing no tea catechin, cyclodextrin, and vitamin C were added.
In addition, drinks of the same components other than tea catechin were used as placebo drinks.
３）試験スケジュール
試験は二重盲検法により実施した。試験スケジュールを図４に示す。いずれの群も各期間の開始時および終了時に血液検査を行った。
Ａ群には対照飲料を１日３本摂取させ、Ｂ群には試験飲料を1日２本、Ｃ群には試験飲料を1日３本摂取させた。各群とも食事とともに1本ずつ摂取させた。
なおＢ群においては、茶カテキン以外の１日当たりの総摂取量をＡ群、Ｃ群と合わせるため、昼食時のみ対照飲料を１本摂取させた。
3) Test schedule The test was performed by a double blind method. The test schedule is shown in FIG. All groups performed blood tests at the beginning and end of each period.
Group A received three control drinks per day, group B received two test drinks per day, and group C received three test drinks per day. Each group was fed one by one with meals.
In addition, in Group B, one control drink was ingested only at lunch, in order to match the total daily intake other than tea catechin with Groups A and C.
４）観察項目
全被験者に対し、血清脂質として総コレステロール(TC)、ＨＤＬ−コレステロール(HDL-C)、ＬＤＬ−コレステロール(LDL-C)、中性脂肪(TG)を測定した。
ＴＣ,ＨＤＬ−ＣおよびＴＧについては酵素法にて測定した。ＬＤＬ−ＣについてはFriedewa1dらの式(LDL-C=TC-HDL-C-TG/5)によって算出した。
また健康状態を確認するため、ＢＵＮ、尿酸、総タンパク、ＡＬＰ、ＧＯＴ、ＧＰＴ、ＬＤＨ、γ−ＧＴＰ、ＣＰＫ、Ｎａ、Ｋ、Ｃａ、Ｃｌ、Ｆｅ、ＵＩＢＣ、フェリチン、ＨｂＡ1ｃ、ヘモグロビン、赤血球数、白血球数、血小板数およびヘマトクリットを測定した。さらに各採血前３日間、食事調査および運動量調査を行った。食事については被験者に食事調査票に記入させ、「五訂日本食品標準成分表」に準拠して栄養計算を行った。運動量については全被験者に歩数計を配布し、１日の総歩数を記入させた。
なお、採血は早朝空腹時に行った。各採血日には医師による診察を行い、体調の変化について観察を行った。
4) Observation items Total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), and neutral fat (TG) were measured as serum lipids for all subjects.
TC, HDL-C and TG were measured by an enzyme method. LDL-C was calculated by the formula of Friedewa1d et al. (LDL-C = TC-HDL-C-TG / 5).
Also, to confirm the health status, BUN, uric acid, total protein, ALP, GOT, GPT, LDH, γ-GTP, CPK, Na, K, Ca, Cl, Fe, UIBC, ferritin, HbA1c, hemoglobin, erythrocyte count, Leukocyte count, platelet count and hematocrit were measured. In addition, a meal survey and a locomotor activity survey were performed for three days before each blood sampling. The subjects were asked to fill out a meal questionnaire, and the nutrition was calculated according to the "Fiveth Edition Japanese Food Standard Composition Table". Regarding the amount of exercise, a pedometer was distributed to all subjects, and the total number of steps per day was recorded.
The blood was collected on an empty stomach in the early morning. On each blood collection day, a medical examination was performed by a doctor to observe changes in physical condition.
５）統計解析
各測定値は平均値±標準偏差で示した。有意差検定はＳＡＳ統計解析プログラムを用い、危険率を５％未満として解析を行った。
各測定値の検定は、正規性が認められた場合、多重比較検定(Dumet法)を行った。正規性が認められなかった場合Stea1法にて検定を行った。
5) Statistical analysis Each measured value was shown as an average value ± standard deviation. Analysis of significance was performed using a SAS statistical analysis program with a risk factor of less than 5%.
In the test of each measured value, when normality was recognized, a multiple comparison test (Dumet method) was performed. When normality was not recognized, the test was performed by the Stea1 method.
６）結果
（１）栄養摂取量・運動量
試験期間中の１日当たりの栄養摂取量および運動量を表５に示す。食事調査・運動量調査は各採血日前、平日３日間の平均値として示した。全体を通して摂取エネルギーの平均値が１６３８〜１８４６ｋｃａＬ／ｄａｙと低かったが、医師による聞き取りの結果、すべての被験者が有職者であり、食習慣として平日朝・昼食は極めて簡単な食事で済まし、平日夜および休日にアルコールとともに多食する傾向があったためと判断された。
各群間のエネルギー摂取量には有意な差は認められなかった。また摂取開始４週時に、Ｃ群(106.1±95.6mg/d1)においてＡ群(198.O±69.3mg/d1)に比してコレステロール摂取量が有意に低かったが、一般的に一時的なコレステロール摂取の多寡が即時に血清コレステロール値に反映されることはなく、実際この時点において各群の血清脂質濃度に差が認められていないことから、特に影響はないものと考えられた。その他の各被験者の栄養摂取量および運動量に差は認められなかった。
6) Results (1) Nutrient intake and exercise The daily nutrition intake and exercise during the test period are shown in Table 5. The diet survey and the exercise amount survey were shown as the average values of three days before each blood sampling and on weekdays. The average value of the energy intake was low throughout the whole, from 1638 to 1846 kcaL / day, but as a result of interviews with the doctors, all the subjects were occupants. And it was judged that there was a tendency to eat a lot with alcohol on holidays.
There was no significant difference in energy intake between each group. At 4 weeks after the start of ingestion, the cholesterol intake was significantly lower in group C (106.1 ± 95.6 mg / d1) than in group A (198.O ± 69.3 mg / d1), but it was generally temporary. The level of cholesterol intake was not immediately reflected in the serum cholesterol level, and in fact, there was no difference in the serum lipid concentration of each group at this time, so it was considered that there was no particular effect. No difference was observed in the nutritional intake and exercise amount of each of the other subjects.
（２）血清脂質
試験期間中の血清脂質関連検査値の推移を表６に示す。Ｃ群(3本/day)では、ＴＣ値が226.9±20.2mg/dL(摂取開始時)から203.0±22.7mg/dL(8週後)と摂取開始時に比べて有意(ρ<O.05 by Dunnet-test)に低下した。
開始８週後のＡ群(対照飲料群)のＴＣ値236.O±19.1mg/dLに対しても有意(ρ<O.01)に低かった。同様にＬＤＬ−Ｃ値も141.6±22.3mg/dL(摂取開始時)から116.9±14.4mg/dL(8週後)と摂取開始時に比べて有意(ρ<O.01)に低下し、開始8週後のＡ群(対照飲料群)のＬＤＬ−Ｃ値147.3±22.3mg/d1に対しても有意(ρ<0.01)
に低かった。
Ｂ群(2本/day)においてもＴＣ値が236.O±25.8mg/d1(摂取開始時)から219.1±21.Omg/d1(8週後)と推移し、摂取開始８週後において、Ａ群(対照飲料群)のＴＣ値236.O±19.1mg/d1に対して低い傾向(ρ<0.1)にあった。一方、ＨＤＬ−Ｃ、ＴＧ、ＨｂＡ1ｃの各数値にはＢ群、Ｃ群とも摂取開始時に比べて有意な差は認められなかった。またＡ群(対照飲料群)に対しても有意な差は認められなかった。
(2) Serum lipid Table 6 shows changes in serum lipid-related test values during the test period. In group C (3 bottles / day), the TC value was 226.9 ± 20.2 mg / dL (at the start of ingestion) to 203.0 ± 22.7 mg / dL (after 8 weeks), which was significantly higher than at the start of ingestion (ρ <O.05 by Dunnet-test).
The TC value of Group A (control drink group) 8 weeks after the start was also significantly (ρ <0.01) lower than the TC value of 236.0 ± 19.1 mg / dL. Similarly, the LDL-C value also decreased significantly (ρ <0.01) from 141.6 ± 22.3 mg / dL (at the start of ingestion) to 116.9 ± 14.4 mg / dL (after 8 weeks) at the start of ingestion. LDL-C value of group A (control drink group) after week was also significant for 147.3 ± 22.3 mg / d1 (ρ <0.01)
Was low.
In the B group (2 bottles / day), the TC value also changed from 236.O ± 25.8 mg / d1 (at the start of ingestion) to 219.1 ± 21.Omg / d1 (after 8 weeks). The TC value of the group A (control drink group) tended to be lower than the TC value of 236.0 ± 19.1 mg / d1 (ρ <0.1). On the other hand, no significant difference was observed in the values of HDL-C, TG, and HbA1c in both the B group and the C group at the start of ingestion. No significant difference was observed with respect to Group A (control drink group).
（３）血液成分・ミネラルおよびその他の所見
被験者の血液成分およびミネラルの推移を表７に示す。摂取期問中、Ｂ群、Ｃ群ともに開始時と比較して、赤血球数、白血球数、血小板数、ヘモグロビン、ヘマトクリット、フェリチンおよびＦｅ、Ｃａ、Ｋ、Ｃｌ、Ｎａの各数値に有意な変化は認められなかった。
また各群間にも有意な差は認められなかった。
後経過観察期間後に、摂取開始時に比してＣ群でＮａの有意(ρ<0.01)な増加(141.7±1.3mg/d1→143.4±1.3mg/d1)が、Ｂ群でＣａの有意(ρ<0.05)な増加(4.7±O.2mg/d1→4.9±O.1mg/d1)が認められたが、ともに正常範囲内であり、医師により医学的に問題ないと判断された。
試験期間中、γ−ＧＴＰ、ＧＯＴ、ＧＰＴにも有意な変化は認められず、医師の診察時に有害事象と思われる所見も一切観察されなかった。
(3) Blood components / minerals and other findings Table 7 shows changes in blood components and minerals of the test subjects. During the intake period, there were no significant changes in the red blood cell count, white blood cell count, platelet count, hemoglobin, hematocrit, ferritin, and Fe, Ca, K, Cl, and Na values in both groups B and C compared to the time of the start. I was not able to admit.
No significant difference was observed between the groups.
After the follow-up period, a significant (ρ <0.01) increase in Na in group C (141.7 ± 1.3 mg / d1 → 143.4 ± 1.3 mg / d1) compared to that at the start of ingestion was significant in Ca in group B (ρ <0.01). <0.05) (4.7 ± 0.2 mg / d1 → 4.9 ± 0.1 mg / d1), but both were within the normal range, and were judged to be medically acceptable by a physician.
During the test period, no significant change was observed in γ-GTP, GOT, and GPT, and no findings considered to be adverse events were observed at the doctor's visit.
７）考察
本試験では、被験者に１本当たり茶ポリフェノール２５０ｍｇ、うち茶カテキンとして１５０ｍｇ(EGCg51.3mg,GCg62.7mg,ECg19.Omg,Cg17.0mg)を含む飲料を、1日２本または３本を８週間摂取させた。したがって１日当たりの摂取量は、Ｂ群で茶ポリフェノール５００ｍｇ、茶カテキンとして３００ｍｇ(EGCg102.6mg, GCg125.4mg, ECg38.Omg, Cg34.Omg)、Ｃ群で茶ポリフェノール７５０ｍｇ、茶カテキンとして４５０ｍｇ(EGCg153.9mg,GCg188.1mg,ECg57.Omg,Cg51.Omg)となる。このＣ群の１日当たり４５０ｍｇの茶カテキン摂取量は、通常の緑茶８〜９杯分の茶カテキン量に相当する。
摂取されたカテキンが食事由来コレステロール、腸管に排泄された内因性のコレメテロールおよび胆汁酸ミセル中のコレステロールと不溶性沈殿を形成することによって、小腸からのコレステロール吸収が阻害され、糞便中に胆汁酸ならびにコレステロールが排泄される。特にエステル型カテキンは胆汁酸ミセルからのコレステロール脱離能が他のカテキン種に比べて高いことから、エステル型カテキンを主として配合している本飲料の効果は、腸管からのコレステロール吸収阻害によるものであると推察される。
また、茶カテキンは腸内乳酸菌を増殖させるなど腸内細菌叢を変化させることが知られている。食事由来の食物繊維は乳酸菌等により容易に資化され、その結果、産生されるプロピオン酸が増加する。産生されたプロピオン酸は肝臓のHMG-CoA synthase活性を阻害し、コレステロール合成を抑制することが報告されていることから、本試験の後経過観察期間後の血清コレステロール値の推移には、この機序の寄与も考えられる。すなわち、茶カテキン摂取期間中は、1)腸管に排出された内因性コレステロールの再取り込み阻害、2)乳酸菌増殖に起因するコレステロール合成阻害、3)胆汁酸が腸管循環阻害を受けたことに起因するコレステロールから胆汁酸への合成の亢進によって、内因性コレステロールプールが低下するとともに胆汁中のコレステロール飽和度も低下すると考えられる。茶カテキン摂取終了後は、内因性コレステロールプールが回復して胆汁酸合成が低下した後、余剰の内因性コレステロールが血中に流出し血清コレステロール値の増加に至ると考えられる。しかしながら茶カテキン摂取開始後、血清コレステロール値の低下が顕著になるまでに４週を要していることを考慮すれば、被験者の血清コレステロール値が摂取開始前に復帰するためには若干の時間的遅延があったものと推察される。
一方、本試験においては茶カテキンによる血清ミネラル値の低下は認められなかった。加えて血清鉄やＵＩＢＣ、ヘモグロビン、ヘマトクリットの各数値にも有意な変化が認められなかった。
この結果は、茶の摂取は微量金属元素の吸収に影響を与えないとするRecordらの報告と一致する。したがって今回の検討は８週間であったが、茶カテキンを配合した茶飲料の摂取は、血清ミネラルの各数値を低下させることなく、長期にわたり摂取可能である。
7) Discussion In this test, two or three drinks containing 250 mg of tea polyphenol per day and 150 mg of tea catechin (EGCg 51.3 mg, GCg 62.7 mg, ECg19.Omg, Cg17.0 mg) per subject were tested. For 8 weeks. Therefore, the daily intake is 500 mg of tea polyphenol and 300 mg of tea catechin (EGCg 102.6 mg, GCg 125.4 mg, ECg38.Omg, Cg34.Omg) in group B, 750 mg of tea polyphenol and 450 mg of tea catechin (EGCg153 in group C). .9 mg, GCg 188.1 mg, ECg57.Omg, Cg51.Omg). The daily intake of 450 mg of tea catechin in the group C corresponds to the amount of tea catechin for 8 to 9 cups of normal green tea.
Ingested catechins form insoluble precipitates with dietary cholesterol, endogenous cholesterol excreted in the intestinal tract and cholesterol in bile acid micelles, thereby inhibiting cholesterol absorption from the small intestine and causing bile acids and cholesterol in the feces. Is excreted. In particular, ester-type catechins have a higher ability to release cholesterol from bile acid micelles than other catechins.Therefore, the effect of this beverage mainly containing ester-type catechins is due to inhibition of cholesterol absorption from the intestinal tract. It is presumed that there is.
In addition, it is known that tea catechin changes intestinal flora, such as by growing intestinal lactic acid bacteria. Dietary fiber derived from diet is easily assimilated by lactic acid bacteria and the like, and as a result, the amount of propionic acid produced increases. It has been reported that the produced propionic acid inhibits hepatic HMG-CoA synthase activity and suppresses cholesterol synthesis. Introductory contributions are also conceivable. That is, during the period of tea catechin intake, 1) inhibition of reuptake of endogenous cholesterol excreted into the intestinal tract, 2) inhibition of cholesterol synthesis caused by lactic acid bacteria growth, and 3) inhibition of bile acids by intestinal circulation. It is thought that the enhanced synthesis of bile acids from cholesterol lowers the endogenous cholesterol pool and also lowers the cholesterol saturation in bile. It is considered that after the end of tea catechin intake, the endogenous cholesterol pool recovers and bile acid synthesis decreases, and then excess endogenous cholesterol flows out into the blood, leading to an increase in serum cholesterol level. However, taking into account that it takes 4 weeks after the start of tea catechin intake until the decrease in serum cholesterol level becomes remarkable, it takes some time for the serum cholesterol level of the subject to return before the start of intake. It is presumed that there was a delay.
On the other hand, in this test, no decrease in serum mineral level due to tea catechin was observed. In addition, there were no significant changes in serum iron, UIBC, hemoglobin, and hematocrit.
This result is consistent with the report by Record et al. That tea consumption does not affect the absorption of trace metal elements. Therefore, although this study was conducted for 8 weeks, the ingestion of tea beverages containing tea catechins can be ingested for a long time without lowering the serum mineral values.
なお、脂質二重層に対する親和性と立体化学的構造が没食子酸エステル型カテキン類の間で異なることが報告されている( K. Kajiyaら：Biosci. Biotech. Biochem. 2001, 65, pp.2638-2643)。このことからすると、これらの差がＥＣｇ、ＥＧＣｇ、Ｃｇ及びＧＣｇの間のコレステロール低下作用の差異に影響しているものと考えられる。 It has been reported that the affinity and stereochemical structure for lipid bilayers differ between gallate ester catechins (K. Kajiya et al .: Biosci. Biotech. Biochem. 2001, 65, pp. 2638-). 2643). This suggests that these differences influence the difference in the cholesterol-lowering effect among ECg, EGCg, Cg, and GCg.
＜試験５＞
本試験は、胸管カニューレ挿入ラットを対象として、緑茶カテキン類（エピ体：（−）ＥＣ、（−）ＥＧＣ、（−）ＥＣｇ及び（−）ＥＧＣｇ）及び熱エピマー化カテキン類（非エピ体：（−）Ｃ、（−）ＧＣ、（−）Ｃｇ及び（−）ＧＣｇ）が、コレステロールのリンパ管吸収に及ぼす効果について比較検討した。
<Test 5>
In this test, green tea catechins (epi-forms: (-) EC, (-) ECC, (-) ECg and (-) EGCg) and heat-epimerized catechins (non-epi-forms) were tested in thoracic duct cannulated rats. : (-) C, (-) GC, (-) Cg, and (-) GCg) were compared and studied on the effect of cholesterol on lymphatic absorption.
１）材料
カテキン純品に関しては、（−）ＥＣ、（−）ＥＧＣ及び（−）Ｃは和光純薬工業社製、（−）ＧＣ、（−）Ｃｇ及び（−）ＧＣｇは長良化学工業社（Nagara Science）製、（−）ＥＣｇ及び（−）ＥＧＣｇは栗田工業社製のものを入手した。これらのカテキン類(単一物質)の純度はいずれも９８％以上であった。
また、４-14Ｃ-コレステロール(５５ mCi/mmoL)は、Amersham Pharmacia Biotech社から購入した。
1) Materials Regarding pure catechin, (-) EC, (-) EGC and (-) C are manufactured by Wako Pure Chemical Industries, Ltd., (-) GC, (-) Cg and (-) GCg are manufactured by Nagara Chemical Industry Co., Ltd. (-) ECg and (-) EGCg manufactured by (Nagara Science) were obtained from Kurita Water Industries. The purity of each of these catechins (single substance) was 98% or more.
4- 14 C-cholesterol (55 mCi / mmoL) was purchased from Amersham Pharmacia Biotech.
緑茶カテキン類の混合物は、伊藤園製のテアフラン９０Ｓを用いた。熱エピマー化カテキン類（非エピ体）は、このカテキン混合物を１２０℃で５分間オートクレーブ加熱処理して調製した。
緑茶カテキン類（エピ体）及び熱エピマー化カテキン類（非エピ体）のカテキン組成を表８に示す。この表８を見ると、緑茶カテキン類から調製したエピマー化カテキン類（非エピ体）では、Ｃｇ及びＧＣｇ量が増加していることが確認できる。
The mixture of green tea catechins used was Theafran 90S manufactured by ITO EN. The heat epimerized catechins (non-epimer) were prepared by heating this catechin mixture at 120 ° C. for 5 minutes in an autoclave.
Table 8 shows the catechin compositions of green tea catechins (epi-form) and heat epimerized catechins (non-epi-form). From Table 8, it can be confirmed that the amounts of Cg and GCg are increased in the epimerized catechins (non-epimer) prepared from the green tea catechins.
２）試験内容
８週齢ＳＤラットに、手術までの１週間市販の中国風食事(チャウチャウ)を与えた。これらのラットの頭部くも膜下槽乳糜(にゅうび)への左胸部リンパ管に前もってカニューレを挿入した。
試験乳濁液投与のため胃内部に第二の体内導入カテーテルを置いた。外科的処置後動物を拘束かごに入れ、実験終了まで3.4 mL/hの速度で139 mMのグルコースと85 mMのＮaＣlを含む溶液を胃内部に連続注入した。同じ溶液を飲料水として与えた。翌朝、一定のリンパ流速を持つ動物に3 mLの14Ｃ-コレステロール含有試験乳濁液を、カテキン試料とともに又はなしで投与した。
試験乳濁液(3 mL)は、200 mg のタウロコール酸(複合胆汁酸)ナトリウム、50 mgの脂肪酸を含まないウシアルブミン分画Ｖ、200 mgのトリオレイン、37 kBqの14Ｃ-コレス
テロール及び25 mgのコレステロールを含有していた。該混合物を超音波処理により乳化した。
2) Test content Eight-week-old SD rats were fed a commercially available Chinese-style meal (chow chow) for one week before surgery. The left thoracic lymphatic vessels into the subarachnoid chyle of these rats were pre-cannulated.
A second intravenous catheter was placed inside the stomach for administration of the test emulsion. After the surgical treatment, the animals were placed in a restraining cage, and a solution containing 139 mM glucose and 85 mM NaCl was continuously injected into the stomach at a rate of 3.4 mL / h until the end of the experiment. The same solution was given as drinking water. The next morning, animals with a constant lymphatic flow rate were administered 3 mL of 14 C-cholesterol containing test emulsion with or without catechin samples.
Test emulsion (3 mL) contains 200 mg sodium taurocholate (complex bile acid), 50 mg bovine albumin fraction V without fatty acids, 200 mg triolein, 37 kBq of 14 C-cholesterol and 25 mg It contained mg cholesterol. The mixture was emulsified by sonication.
茶カテキン類及び熱エピマー化カテキン類を投与する場合は、これらのカテキン類を該乳濁液3 mL中にそれぞれ100 mg及び120 mg添加した。カテキン類の含有量(ＥＣｇ、ＥＧＣｇ、Ｃｇ及びＧＣｇの合計)は、熱エピマー化カテキン類では減少するので、カテキン量は茶カテキン類とエピマー化カテキン類間で同じレベルとなるように調節した。
脂質乳濁液中におけるコレステロールに対する全カテキン類のモル比は、約2.5であった。リンパをＥＤＴＡを含む氷冷管で捕集して、放射能を測定した。
なお、動物での研究はすべて、九州大学大学院農学研究院動物実験ガイドライン並びに「動物の保護及び管理に関する法律」(昭和48年10月１日法律第105 号) 及び「実験動物の飼養及び保管等に関する基準」(昭和55年３月27日総理府告示第６号) に従って実施した。
When administering tea catechins and heat epimerized catechins, 100 mg and 120 mg of these catechins were added to 3 mL of the emulsion, respectively. Since the content of catechins (the sum of ECg, EGCg, Cg and GCg) decreased in the heat epimerized catechins, the catechin amount was adjusted to be the same level between the tea catechins and the epimerized catechins.
The molar ratio of total catechins to cholesterol in the lipid emulsion was about 2.5. Lymph was collected in an ice-cold tube containing EDTA and radioactivity was measured.
In addition, all research on animals was conducted using the Animal Experiment Guidelines at the Graduate School of Agriculture, Kyushu University, the “Law on the Protection and Management of Animals” (Act No. 105 of October 1, 1973), and Standards ”(Notification No. 6 of the Prime Minister's Office on March 27, 1980).
図７には、胃内部に脂質乳濁液を投与したラットに対して、コントロール、緑茶カテキン類或いは熱エピマー化カテキン類を投与した各群におけるコレステロールのリンパ管吸収吸収率の経時的変化を示した。
なお、データは６又は７匹のラットの平均値±標準誤差で示し、a,b,cは異なる文字間で有意差があることを示している(Ｐ＜0.05)。
FIG. 7 shows the time-course changes in the absorption rate of cholesterol in the lymphatic vessels in the rats to which the lipid emulsion was administered in the stomach of the control, green tea catechins or heat epimerized catechins. Was.
The data are shown as the mean ± standard error of 6 or 7 rats, and a, b, and c indicate that there is a significant difference between different characters (P <0.05).
（結果）
コントロール群、緑茶カテキン類（（−）ＥＣ、（−）ＥＧＣ、（−）ＥＣｇ及び（−）ＥＧＣｇ）群及び熱エピマー化カテキン類（（−）Ｃ、（−）ＧＣ、（−）Ｃｇ及び（−）ＧＣｇ）群間ではリンパ流速は直線的で、差異は認められなかった(それぞれ175±15 mL/24h、165±16 mL/24h及び154±17 mL/24h)。
カテキン類の投与は、２４時間のリンパ捕集の間コントロール群と比較してコレステロールのリンパへの回復を効果的かつ有意に低下させた(図７参照)。
エピマー化カテキン類は、コレステロール吸収の低下において茶カテキン類よりも効果的かつ有意であった。14Ｃ-コレステロールのリンパへの回復率は、コントロール、緑茶カテキン及び熱エピマー化カテキン群における２４時間のリンパ捕集の間それぞれ40.5±1.6％、24.9±3.0％及び15.2±2.0％であった。
(result)
Control group, green tea catechins ((-) EC, (-) EGC, (-) ECg and (-) EGCg) group and heat epimerized catechins ((-) C, (-) GC, (-) Cg and The lymph flow velocity was linear between the (-) GCg) groups and no difference was observed (175 ± 15 mL / 24h, 165 ± 16 mL / 24h and 154 ± 17 mL / 24h, respectively).
Administration of catechins effectively and significantly reduced the recovery of cholesterol to the lymph during the 24 hour lymphatic collection compared to the control group (see FIG. 7).
Epimerized catechins were more effective and significant in reducing cholesterol absorption than tea catechins. The recovery rate of 14 C-cholesterol to the lymph was 40.5 ± 1.6%, 24.9 ± 3.0% and 15.2 ± 2.0% during the 24-hour lymphatic collection in the control, green tea catechin and heat epimerized catechin groups, respectively.
（考察）
本試験結果より、レトルト処理中に増加した熱エピマー化カテキン類（（−）Ｃ、（−）ＧＣ、（−）Ｃｇ及び（−）ＧＣｇ）が、熱エピマー化する前のカテキン類、すなわち緑茶カテキン類（（−）ＥＣ、（−）ＥＧＣ、（−）ＥＣｇ及び（−）ＥＧＣｇ）よりも血漿コレステロール濃度を効果的に低下させることが分かった。
また、血漿コレステロール濃度がアテローム性動脈硬化症に対する独立のリスク因子であることも立証されていることから(G. Rose and M. Shipley：Brit. Med. J. 1986, 293, pp.306-307)、本試験結果と合わせて検討すると、緑茶カテキン類と熱エピマー化カテキン類の双方とも、血漿コレステロール低下と抗酸化活性とによってアテローム性動脈硬化症の防止に効果を有し、中でも熱エピマー化カテキン類は緑茶カテキン類よりも一層効果的であると考えられる。
なお、熱エピマー化カテキン類の安全性に関しては、緑茶カテキン類及び熱エピマー化カテキン類を含む茶飲料を全カテキン類として450〜900 mg/dayとなるように8〜20週間ヒトに与えたところ、生物化学的血液パラメーターに異常は認められなかったと報告されている(T. Nagaoら：J. Oleo Sci. 2001, 50, pp.717-728)。
(Discussion)
From the test results, the catechins ((−) C, (−) GC, (−) Cg, and (−) GCg) increased during the retort treatment were converted into catechins before thermal epimerization, that is, green tea. It has been found that plasma cholesterol levels are more effectively reduced than catechins ((-) EC, (-) EGC, (-) ECg and (-) EGCg).
Plasma cholesterol levels have also been demonstrated to be an independent risk factor for atherosclerosis (G. Rose and M. Shipley: Brit. Med. J. 1986, 293, pp. 306-307). ), When examined in conjunction with the results of this test, both green tea catechins and heat epimerized catechins have an effect on plasma cholesterol lowering and antioxidant activity to prevent atherosclerosis, and especially heat epimerization Catechins are thought to be more effective than green tea catechins.
Incidentally, regarding the safety of heat epimerized catechins, tea beverages containing green tea catechins and heat epimerized catechins were given to humans for 8 to 20 weeks so that the total catechins became 450 to 900 mg / day. No abnormalities in biochemical blood parameters were reported (T. Nagao et al .: J. Oleo Sci. 2001, 50, pp.717-728).
（実施例１）
テアフラン９０Ｓ（伊藤園製緑茶抽出物、組成は表１参照）を１４５０ｍｇ／Ｌの濃度となるように６０℃の温水に溶解させ、３５℃に冷却後ビタミンＣを３００ｍｇ／Ｌ添加し、次いでサイクロデキストリンを１重量％、重曹を約３００ｍｇ／Ｌを加え、蒸留水で最終的に１ｋｇに調製してカテキン溶液を得た。得られたカテキン溶液を、９５℃に加熱した後、缶に充填して１２３℃・１０分間の加熱処理を行い、下記組成の血清コレステロール低下飲料を作製した。
(Example 1)
Theafran 90S (green tea extract manufactured by ITO EN, see Table 1 for composition) was dissolved in warm water at 60 ° C. to a concentration of 1450 mg / L, cooled to 35 ° C., added with 300 mg / L of vitamin C, and then cyclodextrin. Was added thereto, and about 300 mg / L of sodium bicarbonate was added, and finally adjusted to 1 kg with distilled water to obtain a catechin solution. After heating the obtained catechin solution to 95 ° C., it was filled in a can and heat-treated at 123 ° C. for 10 minutes to prepare a serum cholesterol-lowering beverage having the following composition.
カテキン １５０ｍｇ
（−） ＧＣｇ ６２．７ｍｇ
（−）ＥＧＣｇ ５１．３ｍｇ
（−） ＥＣｇ １９．０ｍｇ
（−） Ｃｇ １７．０ｍｇ
ビタミンＣ ５０ｍｇ
サイクロデキストリン ５００ｍｇ
水 全体を１９０ｍＬに調製
Catechin 150mg
(-) GCg 62.7mg
(-) 51.3 mg of EGCg
(-) ECg 19.0mg
(-) Cg 17.0mg
Vitamin C 50mg
Cyclodextrin 500mg
Adjust the whole water to 190mL
この血清コレステロール低下飲料は、含有するカテキン類がすべてエステル型カテキン類であり（すなわち１００重量％）、エステル型カテキン類の濃度は７８９ｍｇ／Ｌ、エステル型カテキン類中の「（−）ＧＣｇ＋（−）Ｃｇ」の割合は５３．１重量％、また、（−）ＥＣｇの割合は１２．７重量％である。 In this serum cholesterol-lowering beverage, the catechins contained therein were all ester-type catechins (that is, 100% by weight), the concentration of the ester-type catechins was 789 mg / L, and “(−) GCg + (−) ) Cg "is 53.1% by weight, and (-) ECg is 12.7% by weight.
Claims (7)
（１）（−）ＧＣｇ及び（−）Ｃｇの合計含有量が、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇの合計含有量の４０重量％以上である。
（２）（−）ＥＣｇの含有量が、エステル型カテキン類である（−）ＥＧＣｇ、（−）ＥＣｇ、（−）ＧＣｇ及び（−）Ｃｇの合計含有量の２０重量％以下である。
（３）（−）ＧＣｇの含有量が、（−）ＥＣｇの含有量以上である。 (-) EGCg, (-) ECg, (-) GCg and (-) Cg, which are ester-type catechins, are contained in a total amount of 70% by weight or more of the total content of all catechins, and the following (1) to (1): A food or drink having a serum cholesterol lowering effect, which satisfies the condition (3).
(1) The total content of (−) GCg and (−) Cg is 40% by weight of the total content of (−) EGCg, (−) ECg, (−) GCg and (−) Cg, which are ester catechins. % Or more.
(2) The content of (−) ECg is 20% by weight or less of the total content of (−) EGCg, (−) ECg, (−) GCg, and (−) Cg, which are ester catechins.
(3) The content of (-) GCg is not less than the content of (-) ECg.
Ester-type catechins (-) EGCg, (-) ECg, (-) GCg, and (-) A catechin solution containing 500 to 6000 mg / L in total is prepared, and heat-treating this at 80C or higher. A method for producing a beverage having a characteristic serum cholesterol lowering effect.
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| JP2004034129A JP4494033B2 (en) | 2003-02-10 | 2004-02-10 | Serum cholesterol lowering agent, food and drink, and method for producing the same |
| US10/588,792 US20070105798A1 (en) | 2004-02-10 | 2005-02-03 | Method of Converting Base in DNA Sequence |
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| JP2004034129A JP4494033B2 (en) | 2003-02-10 | 2004-02-10 | Serum cholesterol lowering agent, food and drink, and method for producing the same |
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| JP2005365113A Division JP2006104213A (en) | 2003-02-10 | 2005-12-19 | Food or drink used for lowering serum cholesterol and method for producing the same |
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| WO2007020917A1 (en) * | 2005-08-18 | 2007-02-22 | The University Of Tokushima | Agent for enhancing and prolonging utrophin production and processed food comprising the same |
| JP2007112717A (en) * | 2005-10-18 | 2007-05-10 | Ito En Ltd | Method for producing non-epimeric catechin |
| WO2006131326A3 (en) * | 2005-06-07 | 2007-07-19 | Dsm Ip Assets Bv | Novel use of (-)-epigallocatechin gallate |
| JP2007182405A (en) * | 2006-01-10 | 2007-07-19 | Univ Kurume | Ameliorating and treating agent of fatty liver disease |
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| JP2002272373A (en) * | 2002-03-18 | 2002-09-24 | Kao Corp | Method for producing bottled drink |
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| JP2003231684A (en) * | 2002-02-06 | 2003-08-19 | Ichimaru Pharcos Co Ltd | Cholesterol metabolism improving agent |
| JP2004222719A (en) * | 2002-11-29 | 2004-08-12 | Kao Corp | Method for eliminating caffeine from caffeine-containing catechin compound composition |
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| JP2002326932A (en) * | 2001-03-02 | 2002-11-15 | Kao Corp | Body fat combustion promoter |
| JP2003231684A (en) * | 2002-02-06 | 2003-08-19 | Ichimaru Pharcos Co Ltd | Cholesterol metabolism improving agent |
| JP2002272373A (en) * | 2002-03-18 | 2002-09-24 | Kao Corp | Method for producing bottled drink |
| JP2004222719A (en) * | 2002-11-29 | 2004-08-12 | Kao Corp | Method for eliminating caffeine from caffeine-containing catechin compound composition |
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| WO2007020917A1 (en) * | 2005-08-18 | 2007-02-22 | The University Of Tokushima | Agent for enhancing and prolonging utrophin production and processed food comprising the same |
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