JP2003238401A - Medicine and food and beverage for treating, curing or preventing disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having activity on various diseases and improvement of a function, having high safety and useable for as not only medicine, bus also as a food or beverage such as a functional food. <P>SOLUTION: The medicine comprises leucine as an active ingredient. The medicine contains at least one agent among a glyconeogenesis promoter, an agent for reducing adverse effect, a carcinogenesis-preventing agent, a liver regeneration promoter, an arachidonic acid cascade inhibitor, an agent for improving and/or maintaining various organs and a medicine for treating genetic disease. The medicine can be used in a form of the medicine or the food or beverage such as the functional food as the agent for treating, improving and/or preventing various kinds of diseases. <P>COPYRIGHT: (C)2003,JPO

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【発明の属する技術分野】本発明は、ロイシンを有効成
分として含有する、糖新生促進剤、遺伝病治療薬等、各
種疾患の治療、改善及び／又は予防用薬剤に関し、特に
医薬品及び飲食品の形態で、或いは飲食品に含まれた形
態でこの薬剤を好適に使用することができる。TECHNICAL FIELD The present invention relates to a drug for treating, ameliorating and / or preventing various diseases such as a gluconeogenesis promoter, a drug for treating genetic diseases, etc., which contains leucine as an active ingredient, and particularly to pharmaceuticals and foods and drinks. This drug can be preferably used in the form or contained in a food or drink.

【０００２】[0002]

【従来の技術】アミノ酸はそれぞれ細胞の機能に何らか
の影響を与え、ひいては生体、特に人体の機能に影響を
与える。これはアミノ酸が細胞の機能を維持するための
一般的栄養素という以外に、三つの積極的影響が考えら
れる。2. Description of the Related Art Each amino acid has some effect on the function of cells, and in turn affects the function of the living body, especially the human body. This is thought to have three positive effects, in addition to amino acids being general nutrients for maintaining cell function.

【０００３】身体、或いは細胞が疾患や特殊な状態に
置かれると、特にある種のアミノ酸を要求するようにな
り、これを適切に外部から補給してやることにより細胞
や身体の正常化へ回復することを援助する働きがある。
これは細胞或いは身体の恒常性を保つために、細胞或い
は身体全体の維持を目的として、ある細胞或いは組織が
アミノ酸を他の組織から或いは外部から取り込むように
仕組まれているからと考えられる。When the body or cells are placed in a disease or in a special condition, a certain type of amino acid comes to be required, and by appropriately supplementing this from the outside, the cells and the body are restored to normalization. Have a function to assist
This is probably because, in order to maintain the homeostasis of cells or the body, certain cells or tissues are designed to take in amino acids from other tissues or from the outside in order to maintain the cells or the whole body.

【０００４】アミノ酸は栄養素であると同時に種々の
内因性活性物質の原料となるため、アミノ酸がうまく栄
養素として或いは生理活性物質の原料として使われるた
めに、アミノ酸が積極的に細胞或いは人体の機能を変動
させるシグナルを送る。[0004] Amino acids are not only nutrients but also raw materials for various endogenous active substances. Therefore, amino acids can be used as nutrients or as raw materials for physiologically active substances. Send a varying signal.

【０００５】アミノ酸自体が抗酸化能や金属キレート
能等の生理活性を持つ。Amino acids themselves have physiological activities such as antioxidant ability and metal chelating ability.

【０００６】上記及びは遺伝子発現の変化を伴う。
これ等及びの機能を利用して、アミノ酸を投与す
ることによる疾患の予防や治療が考えられる。アミノ酸
はこれまで用いられてきた合成化合物に比してその生理
活性は弱いが、細胞や身体は目的に合わせて、複数の変
化（例えば、遺伝子発現変化）を誘導するような、合目
的にセットになった生理活性を持つ点、栄養素であるた
め、長期投与をしても大きな副作用が起きない点の２点
に合成化合物には無い大きなメリットを持つ。しかも、
数種のアミノ酸の組み合わせや他の栄養素との組み合わ
せによりそのメリットを拡大することができる。特に、
アミノ酸は長期投与が可能であることにより、疾患の予
防、慢性疾患、遺伝性疾患等で一生投与する必要がある
場合等、合成化合物では不可能な医薬品或いは機能性食
品等の飲食品として力を発揮する。The above and are accompanied by changes in gene expression.
Utilizing these and these functions, prevention and treatment of diseases by administering amino acids can be considered. Amino acids have weaker physiological activity than synthetic compounds that have been used up until now, but cells and the body can be purposefully set so as to induce multiple changes (for example, changes in gene expression) according to the purpose. Since it is a nutrient that has a new physiological activity, it has two major advantages that synthetic compounds do not have significant side effects even after long-term administration. Moreover,
The benefits can be expanded by combining several kinds of amino acids and combining with other nutrients. In particular,
Since amino acids can be administered for a long period of time, they are useful as foods and drinks such as pharmaceuticals or functional foods, which are not possible with synthetic compounds, such as when it is necessary to administer amino acids for the prevention of diseases, chronic diseases, inherited diseases, etc. Demonstrate.

【０００７】従来より、肝不全、肝硬変等の肝臓疾患に
対し、種々のアミノ酸製剤が使用されている。例えば、
アミノレバン、モリヘパミン、アミノレバンＥＮ、ヘパ
ンＥＤ、リーバクト顆粒等のアミノ酸混合物が、栄養補
充或いは、血中アミノ酸濃度不均整による障害是正を目
的として使用されている。Conventionally, various amino acid preparations have been used for liver diseases such as liver failure and cirrhosis. For example,
Amino acid mixtures such as aminolevan, molyhepamin, aminolevan EN, hepan ED, and Livact granules are used for the purpose of nutritional supplementation or correction of disorders due to imbalance of amino acid concentration in blood.

【０００８】各種疾患や機能改善に対して、有効な作用
を有し、かつ安全性が高い薬剤で医薬品のみならず、機
能性食品等の飲食品としても使用できる薬剤の開発が求
められている。There is a demand for the development of a drug which has an effective action against various diseases and functional improvements and is highly safe, and which can be used not only as a drug but also as a food or drink such as a functional food. .

【０００９】[0009]

【発明が解決しようとする課題】本発明が解決しようと
する課題は、各種疾患や機能改善に有効で、下記各種の
薬剤の少なくとも一つに含まれ、更に医薬品のみならず
飲食品の形態（機能性食品等）でも使用でき、また飲食
品に使用した形態で使用することができる薬剤を開発す
ることにある。The problem to be solved by the present invention is effective in improving various diseases and functions, and is contained in at least one of the following various drugs. It is to develop a drug that can be used in functional foods and the like and can be used in the form used for food and drink.

【００１０】I 糖新生促進剤 肝臓の糖新生が不全の遺伝病があり、グリコーゲンが肝
臓に蓄積する障害が起きる。この治療法は無い。この遺
伝病の症状を改善することがこの薬剤の目的である。ま
た、低血糖症が種々の原因、例えば就寝時の飢餓状態で
起きる。一般に、グルコースを投与して治療するが、就
寝時のような低血糖長時間に血糖を維持する必要があ
る。一般家庭で、グルコース点滴を行うのは難しく、就
寝前に投与が容易で、就寝中低血糖を防止する薬剤が求
められている。I Gluconogenesis Promoter There is a genetic disease in which hepatic gluconeogenesis is deficient, and a disorder in which glycogen accumulates in the liver occurs. There is no cure for this. It is the purpose of this drug to improve the symptoms of this genetic disease. Also, hypoglycemia occurs for various causes, for example starvation at bedtime. Generally, glucose is administered and treated, but it is necessary to maintain the blood glucose for a long period of low blood glucose such as at bedtime. There is a need for a drug that is difficult to administer glucose drip in a general household, is easy to administer before bedtime, and prevents hypoglycemia during bedtime.

【００１１】II 薬剤の副作用軽減剤及び発癌防止剤 薬剤の副作用により、投薬を中止したり、投薬量を減ら
したりする必要が生じ、充分な治療ができない場合があ
る。特に、高齢者は肝臓の機能が低下しており、副作用
が起き易い。副作用を軽減する薬品としてグルタチオン
がある。これは薬剤の肝毒性を軽減する作用があるが、
薬剤の排出を促進するものではない。蓄積性の高い薬剤
には効果が低い。薬剤の肝臓における代謝を促進する副
作用軽減剤が必要である。II Side-effect-reducing agent and anti-tumor agent for drugs Due to the side-effects of drugs, it may be necessary to discontinue the drug or reduce the dose, resulting in insufficient treatment. In particular, elderly people have reduced liver function and are likely to have side effects. Glutathione is a drug that reduces side effects. This has the effect of reducing the hepatotoxicity of the drug,
It does not promote excretion of the drug. Less effective for highly accumulative drugs. There is a need for side effect-mitigating agents that promote the metabolism of drugs in the liver.

【００１２】また、癌を予防する薬剤は具体的に存在し
ていない。これは長期服用する必要があり、投薬の副作
用の弊害を伴うからである。副作用が無く投薬を継続で
きる発癌防止剤が望まれる。[0012] Further, there is no specific drug for preventing cancer. This is because it has to be taken for a long period of time and is accompanied by adverse side effects of medication. There is a demand for a carcinogenicity preventive agent that can continue administration without side effects.

【００１３】III 肝再生促進剤 肝臓は再生力の強い組織であるが、劇症肝炎や肝硬変に
おいて再生の障害が起きる。また、肝移植時等、即急な
肝再生が必要である。肝再生を促進する薬剤は存在して
おらず、その原因は、肝臓が薬物代謝の中心臓器である
ためである。肝臓の疾患を治療するために、合成薬剤を
投与すると、薬剤が代謝されて活性を失ってしまうケー
スと、代謝されない化合物を投与すると、かえって肝機
能に負荷をかけてしまうケースがあり、肝臓疾患治療薬
を作ることは容易でない。従って、有効な肝再生促進剤
が必要である。III Liver Regeneration Accelerator Although the liver is a tissue with strong regenerative power, regeneration failure occurs in fulminant hepatitis and cirrhosis. In addition, immediate liver regeneration is necessary, such as during liver transplantation. There is no drug that promotes liver regeneration, because the liver is the central organ for drug metabolism. When a synthetic drug is administered to treat a liver disease, the drug is metabolized and loses its activity, and when a compound that is not metabolized is administered, the liver function is rather burdened. Making a remedy is not easy. Therefore, effective liver regeneration promoters are needed.

【００１４】IV アラキドン酸カスケード抑制剤 アラキドン酸カスケードを抑制して、抗炎症作用を示す
薬剤は多く存在している。しかし、慢性的炎症反応を伴
う疾患は、殆どの臓器で存在し、その治療は困難であ
る。自己免疫やウイルスのような容易に排除できない根
本原因により、ある臓器が長期にわたり障害を受け、次
第に病状が悪化してゆく。ステロイドのような一般的抗
炎症剤は一時的に効果があるが、長期に用いると、副作
用が起きる。作用は弱くとも長期使用することのできる
抗炎症剤が必要である。IV Arachidonic Acid Cascade Inhibitors There are many drugs that inhibit the arachidonic acid cascade and exhibit anti-inflammatory effects. However, diseases associated with a chronic inflammatory reaction are present in most organs and their treatment is difficult. A root cause, such as autoimmunity or a virus, which cannot be easily eliminated, damages an organ for a long period of time, and the illness gradually deteriorates. Common anti-inflammatory agents such as steroids are temporarily effective, but with long-term use, side effects occur. There is a need for an anti-inflammatory agent that has a weak action but can be used for a long time.

【００１５】V 各種臓器の機能維持剤 生活習慣病、慢性疾患や発癌のように長期にわたって、
少しずつ細胞・臓器が障害を受ける場合がある。このよ
うな場合は、明らかな生理作用を持つ薬剤を長期投与す
ることにより、細胞や臓器の障害を減弱し、疾患の進行
を遅らせたり、初期の障害を回復したりする治療・予防
法が望まれる。現在、何年にもわたって投与し続けるこ
とのできる薬剤は無い。作用メカニズムが明白でありか
つ何年間も投与しても副作用が起きない薬剤が望まれ
る。V Function-maintaining agents for various organs, such as lifestyle-related diseases, chronic diseases and carcinogenesis,
The cells and organs may be damaged little by little. In such cases, a long-term administration of a drug having a clear physiological action is desired to be a treatment / prevention method that attenuates the damage of cells and organs, delays the progression of the disease, and recovers the initial damage. Be done. Currently, no drug can be given over many years. A drug is desired which has a clear mechanism of action and causes no side effects even when administered for many years.

【００１６】VI 遺伝病治療薬 遺伝病の根本治療は障害のある遺伝子に対応する遺伝子
治療しか無い。現在は未だ遺伝子治療が実用化されてい
ない。しかし、苦しんでいる遺伝病患者は多数存在す
る。遺伝子疾患により生じる障害を対処療法ではある
が、少しでも改善できる薬剤が望まれる。VI Remedies for Genetic Diseases The only basic treatment for genetic diseases is gene therapy corresponding to the defective gene. At present, gene therapy has not been put to practical use. However, many genetically ill patients suffer. Although it is a coping therapy for a disorder caused by a genetic disease, a drug capable of improving even a little is desired.

【００１７】[0017]

【課題を解決するための手段】本発明者等は、このよう
な状況に鑑み、有効性が高く、安全性面でも問題の無い
（飲食品としての使用が可能）、注射投与等非経口投与
のみならず経口投与でも有効な物質であるアミノ酸のう
ち、中でも細胞に強い生理活性シグナルを送ることが予
想されているロイシンの薬効分子作用機序について鋭意
検討してきた。ロイシンの細胞に及ぼす遺伝子発現変化
を調べた結果、特異的な遺伝子発現制御があることが判
明し、これまで予想しなかったような幾つかの疾患に対
しても治療薬や機能改善薬として有用であることを類推
できる知見を得て本発明に至った。In view of such a situation, the present inventors have found that they are highly effective and have no safety problems (they can be used as food and drink), parenteral administration such as injection administration. Among the amino acids that are effective substances not only for oral administration, leucine, which is expected to send a strong bioactive signal to cells, has been thoroughly studied. As a result of investigating changes in gene expression of leucine on cells, it was revealed that there is specific gene expression regulation, and it is useful as a therapeutic drug or function improving drug even for some diseases that were unexpected The present invention has been accomplished based on the knowledge that the above can be inferred.

【００１８】以下に、ロイシンの肝細胞に及ぼす遺伝子
発現変化の知見を示す。これ等の事実から導き出される
有用性から本発明を完成するに至った。The findings of the gene expression changes of leucine on hepatocytes are shown below. The present invention has been completed from the usefulness derived from these facts.

【００１９】本発明は、ロイシン、特にＬ−ロイシンが
単独で、細胞の遺伝子発現を変化させることを測定する
ことにより、ロイシンの直接薬理作用を明らかにし、ロ
イシンの医薬品又は飲食品（機能性食品等）としての利
用性を見出したものである。The present invention clarifies the direct pharmacological action of leucine by measuring that leucine, particularly L-leucine, alone alters the gene expression of cells, and the drug, food or drink (functional food) of leucine is clarified. Etc.) has been found to be useful.

【００２０】即ち、本発明はロイシンを有効成分として
含有することに特徴を有する下記薬剤の少なくとも一つ
に含まれる薬剤に存する。That is, the present invention resides in a drug contained in at least one of the following drugs characterized by containing leucine as an active ingredient.

【００２１】糖新生促進剤；薬剤の副作用軽減剤；発癌
防止剤；肝再生促進剤；アラキドン酸カスケード抑制
剤；各種臓器の機能改善及び／又は維持剤；並びに遺伝
病治療薬。Gluconogenesis promoters; drug side-effect reducing agents; carcinogenic agents; liver regeneration promoters; arachidonic acid cascade inhibitors; various organ function improving and / or maintaining agents; and therapeutic agents for genetic diseases.

【００２２】本発明の薬剤は医薬品の形態又は飲食品
（例えば、機能食品等）の形態で使用することができ
る。The drug of the present invention can be used in the form of pharmaceuticals or foods and drinks (for example, functional foods).

【００２３】ロイシンとしては光学活性体やラセミ体を
使用することができるが、天然に存する点でＬ−ロイシ
ンを使用するのが好ましい。As leucine, an optically active substance or a racemic substance can be used, but it is preferable to use L-leucine because it exists naturally.

【００２４】医薬品として使用する場合、静脈注射剤、
輸液製剤等非経口投与用製剤として使用することもでき
るが、経口製剤として使用することができる。When used as a pharmaceutical, an intravenous injection,
Although it can be used as a parenteral preparation such as an infusion preparation, it can be used as an oral preparation.

【００２５】本発明の薬剤は特に、肝臓疾患、遺伝性疾
患、薬物中毒等の各種疾患用の薬剤として好適である。The drug of the present invention is particularly suitable as a drug for various diseases such as liver disease, genetic disease and drug addiction.

【００２６】[0026]

【発明の実施の形態】以下に、本発明の実施の形態につ
いて説明する。BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below.

【００２７】本発明はロイシンを有効成分として使用す
る薬剤であるが、生体内、即ち動物、特にヒトの体内に
投与して、各種疾患や機能障害に対して治療、改善或い
は予防をするための薬剤である。The present invention is a drug using leucine as an active ingredient, which is used for treating, ameliorating or preventing various diseases and functional disorders by administering it in vivo, that is, in the body of animals, especially humans. It is a drug.

【００２８】本発明で用いられるロイシンは、市販品、
合成品、その他製法に関係なく使用され得る。また、前
述の如くＤ体、Ｌ体、ＤＬ体の何れも使用可能である
が、天然に存在するという点で、特にＬ体を好ましく使
用することができる。The leucine used in the present invention is a commercially available product,
It can be used regardless of the synthetic method and other manufacturing methods. Further, as described above, any of D-form, L-form and DL-form can be used, but the L-form can be particularly preferably used in that it naturally exists.

【００２９】本発明においてロイシンは、本発明に含ま
れる薬剤成分として使用されるが、特に肝臓疾患、遺伝
性疾患、薬物中毒に対する治療、改善及び／又は予防効
果が期待できる。In the present invention, leucine is used as a drug component contained in the present invention, and it can be expected to have a therapeutic, ameliorating and / or preventive effect on liver diseases, genetic diseases and drug poisoning.

【００３０】ロイシンの生体内への投与により下記のよ
うな改善の作用が与えられる。Administration of leucine in vivo gives the following improving action.

【００３１】I．糖新生促進剤 ロイシンは細胞のGlucose-6-phosphataseの発現亢進及
びGlycogen synthetase2の発現低下を誘導する。この二
つの作用から、ロイシンは肝細胞に対して糖新生を促進
するシグナルを送ることが分かった。Glucose-6-phosph
ataseは糖新生に関わる重要な酵素で、Glucose-6-phosp
hateをglucoseに変換する。低血糖時には糖新生が働
き、エネルギー源であるグルコースの血中濃度の恒常性
を担っている。グルコースは脳や赤血球のほぼ唯一のエ
ネルギー源で、血中のグルコース濃度維持は重要であ
る。低血糖になると、脳の働きが低下し、これが極端に
なると、失神から死に到る場合がある。また、Glucose-
6-phosphataseの変異により、グリコーゲンからの糖新
生が阻害され、グリコーゲンが蓄積する種々の遺伝病
（glycogen storage disease）が知られている(Akanum
a, J.; Nishigaki, T.; Fujii, K.; Matsubara, Y.; In
ui, K.; Takahashi, K.; Kure, S.; Suzuki, Y.; Ohur
a, T.; Miyabayashi, S.; Ogawa, E.; Iinuma, K.; Oka
da, S.; Narisawa, K.: Glycogen storage disease typ
e Ia: molecular diagnosis of 51 Japanesepatients a
nd characterization of splicing mutations by analy
sis of ectopically transcribed mRNA from lymphobla
stoid cells. Am. J. Med. Genet. 91: 107-112, 2000
等参照。)。I. The gluconeogenesis promoter leucine induces up-regulation of Glucose-6-phosphatase and down-regulation of Glycogen synthetase 2 in cells. From these two actions, it was found that leucine sends a signal that promotes gluconeogenesis to hepatocytes. Glucose-6-phosph
atase is an important enzyme involved in gluconeogenesis, Glucose-6-phosp
Convert hate to glucose. During hypoglycemia, gluconeogenesis works and plays a role in the homeostasis of blood glucose concentration, which is an energy source. Glucose is almost the sole energy source of the brain and red blood cells, and maintaining glucose concentration in blood is important. When hypoglycemia occurs, the function of the brain deteriorates, and when it becomes extreme, fainting may result in death. Also, Glucose-
Mutations in 6-phosphatase inhibit gluconeogenesis from glycogen, and various genetic diseases in which glycogen accumulates are known (Akanum).
a, J .; Nishigaki, T .; Fujii, K .; Matsubara, Y .; In
ui, K .; Takahashi, K .; Kure, S .; Suzuki, Y .; Ohur
a, T .; Miyabayashi, S .; Ogawa, E .; Iinuma, K .; Oka
da, S .; Narisawa, K .: Glycogen storage disease typ
e Ia: molecular diagnosis of 51 Japanese patients a
nd characterization of splicing mutations by analy
sis of ectopically transcribed mRNA from lymphobla
stoid cells. Am. J. Med. Genet. 91: 107-112, 2000
See also. ).

【００３２】ロイシンの肝臓に対する、糖新生亢進作用
は、glycogen storage diseaseの改善に有用であろう。
遺伝病は長期投与が必要であり、副作用が無いロイシン
は有効な治療薬となることが期待できる。極度の低血糖
や、長期低血糖が弊害を招くことがあり、ロイシンは低
血糖ショック時の補助療法として使用できる。The gluconeogenic action of leucine on the liver may be useful for amelioration of glycogen storage disease.
Genetic diseases require long-term administration, and leucine, which has no side effects, can be expected to be an effective therapeutic drug. Extreme hypoglycemia and long-term hypoglycemia can be detrimental and leucine can be used as an adjunct therapy during hypoglycemic shock.

【００３３】II．薬剤の副作用軽減剤及び発癌防止剤 ロイシンはAndrosterone UDP-glucuronosyltransferase
の発現を亢進する。また、aflatoxin B1 aldehyde redu
ctaseの発現を亢進する。II. Androsterone UDP-glucuronosyltransferase is a drug side effect reducing agent and carcinogenic agent leucine.
Expression is enhanced. Also, aflatoxin B1 aldehyde redu
Enhances ctase expression.

【００３４】Androsterone UDP-glucuronosyltransfera
seは多くの脂溶性、外来性及び内因性の低分子脂溶性物
質に核酸の糖を転移して（Glucuronidation、グルクロ
ン酸抱合）水溶性化合物として排出する解毒メカニズム
が存在し、UDP-glucuronosyltransferaseがGlucuronida
tionを触媒する。UDP-glucuronosyltransferaseの変異
による疾患が知られており、胆汁への解毒機構が低下
し、高ビリルビン血症となる。（OMIM、UDP-glucuronos
yltransferase）。Ardosteroneの代謝に関与するグルク
ロン酸抱合はAndrosterone UDP-glucuronosyltransfera
seが肝臓で行っている（Pirog EC, Clark RV, Collins
DC. Androgen UDP-glucuronyl transferase activity i
s found primarily in liver in the rat. J Androl 19
93 Jan-Feb;14(1):2-8参照。）。Androsterone UDP-glucuronosyltransfera
se has a detoxification mechanism that transfers sugar of nucleic acid to many lipid-soluble, exogenous and endogenous low-molecular fat-soluble substances (Glucuronidation, glucuronidation) and discharges it as a water-soluble compound, and UDP-glucuronosyltransferase
catalyze tion. A disease caused by a mutation in UDP-glucuronosyltransferase is known, and the mechanism of detoxification into bile is reduced, resulting in hyperbilirubinemia. (OMIM, UDP-glucuronos
yltransferase). Androsterone UDP-glucuronosyltransfera is involved in glucuronidation involved in metabolism of Ardosterone
se in the liver (Pirog EC, Clark RV, Collins
DC. Androgen UDP-glucuronyl transferase activity i
s found primarily in liver in the rat. J Androl 19
See 93 Jan-Feb; 14 (1): 2-8. ).

【００３５】グルクロン酸抱合は薬物の副作用に関係
し、グルクロン酸抱合が阻害されると薬物の副作用を生
じる（Sharp S, Mak LY, Smith DJ, Coughtrie MW. 、I
nhibition of human and rabbit liver steroid and xe
nobiotic UDP-glucuronosyltransferases by tertiary
amine drugs--implications for adverse drug reactio
ns. Xenobiotica 1992 Jan;22(1):13-25参照。）。Glucuronidation is associated with side effects of drugs, and inhibition of glucuronidation causes side effects of drugs (Sharp S, Mak LY, Smith DJ, Coughtrie MW., I.
nhibition of human and rabbit liver steroid and xe
nobiotic UDP-glucuronosyltransferases by tertiary
amine drugs--implications for adverse drug reactio
See ns. Xenobiotica 1992 Jan; 22 (1): 13-25. ).

【００３６】よって、ロイシン投与によりグルクロン酸
抱合活性を増加させ、薬剤の副作用軽減させたり、グル
クロン酸抱合の低下した患者の障害を軽減することが期
待できる。Therefore, it is expected that the administration of leucine will increase the glucuronidation activity, reduce the side effects of the drug, and alleviate the disorders of patients with reduced glucuronidation.

【００３７】アルデヒド（aldehydes）及びケトン（ket
ones）の解毒に多くの酵素が関与しているが、 aldoket
oreductases (AKRs)もその一種である（Ireland, L.
S.; Harrison, D. J.; Neal, G. E.; Hayes, J. D. : M
olecular cloning, expressionand catalytic activity
of a human AKR7 member of the aldo-keto reductase
superfamily: evidence that the major 2-carboxyben
zaldehyde reductase from human liver is a homologu
e of rat aflatoxin B(1)-aldehyde reductase.Bioche
m. J. 332: 21-34, 1998参照。）。AKRsの中でaflatoxi
nの解毒に関する酵素としてaflatoxin B1 aldehyde red
uctase（AFAR）がラットから発見された。Aldehydes and ketones
many enzymes are involved in the detoxification of ones)
Oreductases (AKRs) are one of them (Ireland, L.
S .; Harrison, DJ; Neal, GE; Hayes, JD: M
olecular cloning, expressionand catalytic activity
of a human AKR7 member of the aldo-keto reductase
superfamily: evidence that the major 2-carboxyben
zaldehyde reductase from human liver is a homologu
e of rat aflatoxin B (1) -aldehyde reductase.Bioche
m. J. 332: 21-34, 1998. ). Aflatoxi in AKRs
aflatoxin B1 aldehyde red as an enzyme for detoxification of n
uctase (AFAR) was found in rats.

【００３８】AFARは炭素原子に隣接するketone groupを
持つdicarbonyl-containing compounds with 9,10-phen
anthrenequinone, acenaphthenequinone及びcamphorqui
noneを良い基質としている（Ellis EM, Hayes JD. 、Su
bstrate specificity of anaflatoxin-metabolizing al
dehyde reductase. Biochem J 1995 Dec 1;312 ( Pt2):
535-41参照。）。Aflatoxinは強力な発癌物質である
が、aflatoxin B1 aldehyde reductaseはこれを解毒
し、発癌を抑制する（Kelly VP, Ellis EM, MansonMM,
Chanas SA, Moffat GJ, McLeod R, Judah DJ, Neal GE,
Hayes JD. Chemoprevention of aflatoxin B1 hepatoc
arcinogenesis by coumarin, a natural benzopyrone t
hat is a potent inducer of aflatoxin B1-aldehyde r
eductase, the glutathione S-transferase A5 and P1
subunits, and NAD(P)H:quinone oxidoreductase in ra
t liver. Cancer Res 2000 Feb 15;60(4):957-69、及び
HayesJD, Judah DJ, Neal GE. 、Resistance to aflato
xin B1 is associated withthe expression of a novel
aldo-keto reductase which has catalytic activity
towards a cytotoxic aldehyde-containing metabolite
of the toxin. Cancer Res 1993 Sep 1;53(17):3887-9
4等参照）。AFAR is a dicarbonyl-containing compounds with 9,10-phen having a ketone group adjacent to a carbon atom.
anthrenequinone, acenaphthenequinone and camphorqui
none is a good substrate (Ellis EM, Hayes JD., Su
bstrate specificity of anaflatoxin-metabolizing al
dehyde reductase. Biochem J 1995 Dec 1; 312 (Pt2):
See 535-41. ). Aflatoxin is a powerful carcinogen, but aflatoxin B1 aldehyde reductase detoxifies it and suppresses carcinogenesis (Kelly VP, Ellis EM, MansonMM,
Chanas SA, Moffat GJ, McLeod R, Judah DJ, Neal GE,
Hayes JD. Chemoprevention of aflatoxin B1 hepatoc
arcinogenesis by coumarin, a natural benzopyrone t
hat is a potent inducer of aflatoxin B1-aldehyde r
eductase, the glutathione S-transferase A5 and P1
subunits, and NAD (P) H: quinone oxidoreductase in ra
t Liver. Cancer Res 2000 Feb 15; 60 (4): 957-69, and
HayesJD, Judah DJ, Neal GE., Resistance to aflato
xin B1 is associated with the expression of a novel
aldo-keto reductase which has catalytic activity
towards a cytotoxic aldehyde-containing metabolite
of the toxin. Cancer Res 1993 Sep 1; 53 (17): 3887-9
4 etc.).

【００３９】ロイシン投与により、aldoketoreductases
を誘導し、対応する薬物の副作用や発癌を抑制すること
が期待できる。この他、ロイシンはcytochrome P450 4F
1の発現亢進する。P450は薬物代謝に関連する。By administration of leucine, aldoketoreductases
It can be expected to induce side effects and suppress side effects of corresponding drugs and carcinogenesis. In addition, leucine is cytochrome P450 4F
Upregulation of 1 P450 is associated with drug metabolism.

【００４０】以上、肝臓は薬物代謝の中心である。肝機
能が低下している患者や高齢者が肝での薬物代謝が不全
のため、治療目的の薬剤を投与することができなかった
り、充分な投与量を与えられない場合が生じる。このよ
うな投薬時のロイシンを事前に或いは同時投与すること
により、副作用を軽減して充分治療が可能となる。ま
た、アミノ酸で、体内成分であり、副作用を起こすこと
なく長期間投与することが可能である。既に、ウイルス
感染による慢性肝炎や、肝硬変患者は、高い発現リスク
をもっている。この場合、外部からの発癌性物質特にア
フラトキシンの摂取や、活性酸素の発生等により生じる
遺伝子変異が発癌のきっかけとなる。ロイシンの長期摂
取によりこの発癌リスクを軽減することができる。As described above, the liver is the center of drug metabolism. In patients with reduced liver function or elderly people, the drug metabolism in the liver is insufficient, and thus it may not be possible to administer the drug for therapeutic purposes or the patient may not be given a sufficient dose. By administering leucine at the time of such administration in advance or simultaneously, side effects can be reduced and sufficient treatment can be performed. In addition, it is an amino acid, a component of the body, and can be administered for a long period of time without causing side effects. Already, patients with chronic hepatitis due to viral infection and cirrhosis have a high risk of development. In this case, gene mutation caused by ingestion of a carcinogen from the outside, particularly aflatoxin, generation of active oxygen, etc. triggers carcinogenesis. Prolonged intake of leucine can reduce this carcinogenic risk.

【００４１】一方、ロイシンはAlcohol dehydrogenase
3 (Adh3) の発現を低下する。On the other hand, leucine is Alcohol dehydrogenase.
Decrease expression of 3 (Adh3).

【００４２】Adh3はアルコールを代謝しアセトアルデヒ
ドを産生する。Adh3には多型があり、この活性の高い遺
伝子型は種々の癌発生リスクが高いという報告がある
（Freudenheim JL, Ambrosone CB, Moysich KB, Vena J
E, Graham S, Marshall JR, Muti P, Laughlin R, Nemo
to T, Harty LC, Crits GA, Chan AW, Shields PG. 、A
lcohol dehydrogenase 3 genotype modification of th
e association of alcohol consumption with breast c
ancer risk.、 Cancer Causes Control 1999 Oct;10
(5):369-77；Harty LC, Caporaso NE, Hayes RB, Winn
DM, Bravo-Otero E, Blot WJ, Kleinman DV, Brown LM,
Armenian HK, Fraumeni JF Jr, Shields PG. Alcohol
dehydrogenase 3 genotype and risk of oral cavity a
nd pharyngeal cancers. J Natl Cancer Inst 1997 Nov
19;89(22):1698-705；Schwartz SM, Doody DR, Fitzgi
bbons ED, Ricks S, Porter PL, Chen C. 、Oral squam
ous cell cancer risk in relation to alcohol consum
ption and alcohol dehydrogenase-3 genotypes.Cancer
Epidemiol Biomarkers Prev 2001 Nov;10(11):1137-44
等参照。）。Adh3 metabolizes alcohol to produce acetaldehyde. There are polymorphisms in Adh3, and genotypes with high activity have been reported to be at high risk of developing various cancers (Freudenheim JL, Ambrosone CB, Moysich KB, Vena J
E, Graham S, Marshall JR, Muti P, Laughlin R, Nemo
to T, Harty LC, Crits GA, Chan AW, Shields PG., A
lcohol dehydrogenase 3 genotype modification of th
e association of alcohol consumption with breast c
ancer risk., Cancer Causes Control 1999 Oct; 10
(5): 369-77 ； Harty LC, Caporaso NE, Hayes RB, Winn
DM, Bravo-Otero E, Blot WJ, Kleinman DV, Brown LM,
Armenian HK, Fraumeni JF Jr, Shields PG. Alcohol
dehydrogenase 3 genotype and risk of oral cavity a
nd pharyngeal cancers. J Natl Cancer Inst 1997 Nov
19; 89 (22): 1698-705; Schwartz SM, Doody DR, Fitzgi
bbons ED, Ricks S, Porter PL, Chen C., Oral squam
ous cell cancer risk in relation to alcohol consum
ption and alcohol dehydrogenase-3 genotypes.Cancer
Epidemiol Biomarkers Prev 2001 Nov; 10 (11): 1137-44
See also. ).

【００４３】アルコールの多飲者がアルコール性肝臓疾
患や肝硬変になるリスクもADH3*2ホモ型は高い（Monzon
i A, Masutti F, Saccoccio G, Bellentani S, Tiribel
li C, Giacca M. 、Genetic determinants of ethanol-
induced liver damage. MolMed 2001 Apr;7(4):255-62
参照。）。[0043] ADH3 * 2 homotype also has a high risk of alcoholic liver disease and cirrhosis in people who drink a lot of alcohol (Monzon).
i A, Masutti F, Saccoccio G, Bellentani S, Tiribel
li C, Giacca M., Genetic determinants of ethanol-
induced liver damage. MolMed 2001 Apr; 7 (4): 255-62
reference. ).

【００４４】これにより、ADHは酸素ストレス障害を促
進する。ロイシンによるADH活性抑制は発癌や肝臓疾患
等、種々の疾患発生、増悪の防止となる。前述のウイル
ス性慢性肝炎や肝硬変患者のように、発癌リスクの高い
人を対象に、更に飲酒の習慣がある人はロイシンの長期
投与により発癌のリスクを軽減できる。ADH thus promotes oxygen stress disorders. Suppression of ADH activity by leucine prevents the development and exacerbation of various diseases such as carcinogenesis and liver disease. For people with a high risk of carcinogenesis, such as those with chronic viral hepatitis or cirrhosis, those who have a habit of drinking alcohol can reduce the risk of carcinogenesis by long-term administration of leucine.

【００４５】III．肝再生促進剤 肝臓は薬物代謝の中心臓器である。肝臓の疾患を治療す
るために、合成薬剤を投与すると、薬剤が代謝されて活
性を失ってしまうケースと、代謝されない化合物を投与
すると、かえって肝機能に負荷をかけてしまうケースが
あり、肝臓疾患治療薬を作ることは容易でない。その
点、アミノ酸は肝臓にとって、恒常的システムの中で処
理され、副作用や、活性を失う危険性が低い。肝臓治療
薬としてアミノ酸は有効である。III. Liver Regeneration Promoter The liver is a central organ for drug metabolism. When a synthetic drug is administered to treat a liver disease, the drug is metabolized and loses its activity, and when a compound that is not metabolized is administered, the liver function is rather burdened. Making a remedy is not easy. In that regard, amino acids are processed by the liver in a homeostatic system, and there is a low risk of side effects and loss of activity. Amino acids are effective as liver therapeutic agents.

【００４６】ロイシンはLiver activating protein (LA
P又はNF-IL6又はCCAAT/enhancer-binding protein, bet
a) の発現を亢進する。LAPのノックアウトマウスで肝再
生の遅延が報告されている（Greenbaum, L. E.; Li,
W.; Cressman, D. E.; Peng, Y.; Ciliberto, G.; Pol
i, V.; Taub, R. : J. Clin. Invest. 102: 996-1007,
1998参照。）。LAPはインターロイキン６により誘導さ
れる転写因子で、インターロイキン６は肝再生の誘導因
子の１つと考えられている。インターロイキン６投与は
発熱や悪寒等種々の副作用を生じる。ロイシン投与によ
りLAPが誘導されるということは、ロイシンを長期に副
作用なく投与して、肝移植時の再生促進や、肝障害時の
回復促進が期待できる。Leucine is a liver activating protein (LA
P or NF-IL6 or CCAAT / enhancer-binding protein, bet
enhances the expression of a). Delayed liver regeneration has been reported in LAP knockout mice (Greenbaum, LE; Li,
W .; Cressman, DE; Peng, Y .; Ciliberto, G .; Pol
i, V .; Taub, R .: J. Clin. Invest. 102: 996-1007,
See 1998. ). LAP is a transcription factor induced by interleukin 6, and interleukin 6 is considered to be one of the inducers of liver regeneration. Administration of interleukin 6 causes various side effects such as fever and chills. Induction of LAP by administration of leucine means that leucine can be administered for a long period of time without side effects to promote regeneration during liver transplantation and recovery during liver injury.

【００４７】ロイシンはまたAsparaginyl-tRNA sytheta
se, cytoplasmicの発現を亢進する。Leucine is also Asparaginyl-tRNA sytheta
It enhances se and cytoplasmic expression.

【００４８】Asparaginyl-tRNA sythetaseを始めとする
aminoacyl tRNA sythetase活性は身体の状況で変化す
る。例えば、絶食時に増加し、加齢により低下する（Or
lovskaia NN, Veseliuvskaia LD, Gulyi MF. 、Amino-t
RNA-synthetase activity of rabbit muscles in fasti
ng and agingUkr Biokhim Zh 1980 May-Jun;52(3):325-
8参照。）。肝臓の再生時にaminoacyl tRNA sythetase
活性が亢進する（Del Monte U, Capaccioli S, Neri Ci
ni G, Perego R, Caldini R, Chevanne M. 、Effects o
f liver regeneration on tRNA contents and aminoacy
l-tRNA synthetaseactivities and sedimentation patt
erns. Biochem J 1986 May 15;236(1):163-9参照。）。
aminoacyl tRNA sythetaseは蛋白質合成過程に不可欠の
酵素であるため、これをロイシンが発現亢進することは
蛋白質合成系の亢進を誘導することになる。種々の組織
障害や臓器移植等における組織再生時、運動、疾患、加
齢等で蛋白合成の増強を必要とする場合はロイシンの投
与は蛋白質合成全体を促進することが期待できる。これ
より、ロイシンはLAP発現亢進及びAsparaginyl-tRNAsyt
hetase, cytoplasmicの発現亢進を介して肝再生の促進
に働くと考えられる。Including Asparaginyl-tRNA sythetase
Aminoacyl tRNA sythetase activity changes depending on the physical condition. For example, it increases at fasting and decreases with age (Or
lovskaia NN, Veseliuvskaia LD, Gulyi MF., Amino-t
RNA-synthetase activity of rabbit muscles in fasti
ng and agingUkr Biokhim Zh 1980 May-Jun; 52 (3): 325-
See 8. ). Aminoacyl tRNA sythetase during liver regeneration
Increased activity (Del Monte U, Capaccioli S, Neri Ci
ni G, Perego R, Caldini R, Chevanne M., Effects o
f liver regeneration on tRNA contents and aminoacy
l-tRNA synthetase activities and sedimentation patt
See erns. Biochem J 1986 May 15; 236 (1): 163-9. ).
Since aminoacyl tRNA sythetase is an essential enzyme in the protein synthesis process, an increase in expression of leucine induces an increase in the protein synthesis system. When it is necessary to enhance protein synthesis due to various tissue disorders, tissue regeneration in organ transplantation, exercise, diseases, aging, etc., administration of leucine can be expected to promote the whole protein synthesis. From this, leucine increased LAP expression and Asparaginyl-tRNAsyt.
It is thought that it plays a role in promoting liver regeneration through increased expression of hetase and cytoplasmic.

【００４９】IV．アラキドン酸カスケード抑制剤 アラキドン酸カスケードに関連する生体内生理活性物質
は、炎症に関連する生体反応を惹起する。抗炎は望まれ
る医薬品であり、多くの医薬品が用いられている。慢性
的炎症反応を伴う疾患は、殆どの臓器で存在し、その治
療は難しい。自己免疫やウイルスのような容易に排除で
きない根本原因により、ある臓器が長期にわたり障害を
受け、次第に病状が悪化してゆく。ステロイドのような
一般的抗炎症剤は一時的に効果があるが、長期用いる
と、副作用が起きる。作用は弱くとも長期使用すること
のできる抗炎症剤も必要である。アミノ酸はこの目的に
合致すると思われる。IV. Arachidonic Acid Cascade Inhibitors In vivo physiologically active substances related to the arachidonic acid cascade elicit biological reactions related to inflammation. Anti-inflammatory is a desired drug, and many drugs are used. Diseases with chronic inflammatory reactions are present in most organs and are difficult to treat. A root cause, such as autoimmunity or a virus, which cannot be easily eliminated, damages an organ for a long period of time, and the illness gradually deteriorates. Common anti-inflammatory agents such as steroids are temporarily effective, but with long-term use, side effects occur. There is also a need for anti-inflammatory agents that have a weak effect but can be used for a long time. Amino acids appear to meet this purpose.

【００５０】ロイシンはnucleobindinの発現を亢進す
る。Nucleobindinはアラキドン酸合成に関与するCycloo
xygenases (COXs)を制御している（Ballif BA, Mincek
NV, Barratt JT, Wilson ML, Simmons DL. 、Interacti
on of cyclooxygenases with an apoptosis- and autoi
mmunity-associated protein. Proc Natl Acad Sci U S
A 1996 May 28;93(11):5544-9参照。）。COXを介して、
種々のアラキドン酸の生理活性、即ち炎症誘発、血管の
収縮、気道の収縮等を抑制する。即ち、ロイシンは抗炎
症、血管拡張、喘息の抑制等が期待できる。また、ロイ
シンはarachidonic acid epoxygenaseの発現を亢進す
る。arachidonic acid epoxygenase＝cytochrome P450
arachidonic acid epoxygenase＝CYP2J2はアラキドン酸
のepoxidationを行いepoxyeicosatrienoic acidsを生成
する酵素である。CYP2J2 mRNAは心臓で強い発現をして
おり、肝臓、回腸、空腸、大腸、腎臓で弱い発現をして
いる。ヒト心臓でepoxyeicosatrienoic acidsを介して
心臓の生理において重要な働きをしていると思われる
（Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC.M
olecular cloning and expression of CYP2J2, a human
cytochrome P450 arachidonic acid epoxygenase high
ly expressed in heart. J Biol Chem 1996 Feb16;271
(7):3460-8参照。）。更に、CYP2J2は肺に存在し、epox
yeicosatrienoicacidsを介して気管支平滑筋の収縮圧、
気道上皮細胞のイオン透過及び肺血管の収縮圧を調節す
る。また、中枢微細血管の血流調節に関与する（Alkaye
d NJ, Birks EK, Hudetz AG, Roman RJ, Henderson L,
Harder DR. Inhibition of brainP-450 arachidonic ac
id epoxygenase decreases baseline cerebral blood f
low. Am J Physiol 1996 Oct;271(4 Pt 2):H1541-6参
照。）。肝臓でもarachidonic acid epoxygenaseがアラ
キドン酸代謝に関与し、恒常性維持に重要な働きをして
いる（Rifkind AB, Lee C, Chang TK, Waxman DJ 、Ara
chidonic acid metabolism by human cytochrome P450s
2C8, 2C9, 2E1, and 1A2: regioselectiveoxygenation
and evidence for a role for CYP2C enzymes in arac
hidonic acid epoxygenation in human liver microsom
es. Arch Biochem Biophys 1995 Jul10;320(2):380-9参
照。）。Leucine enhances the expression of nucleobindin. Nucleobindin is involved in arachidonic acid synthesis Cycloo
Controls xygenases (COXs) (Ballif BA, Mincek
NV, Barratt JT, Wilson ML, Simmons DL., Interacti
on of cyclooxygenases with an apoptosis- and autoi
mmunity-associated protein.Proc Natl Acad Sci US
A 1996 May 28; 93 (11): 5544-9. ). Via COX
It suppresses the physiological activity of various arachidonic acids, ie, inflammation induction, blood vessel contraction, airway contraction, etc. That is, leucine can be expected to have anti-inflammatory properties, vasodilation, and asthma suppression. Leucine also enhances the expression of arachidonic acid epoxygenase. arachidonic acid epoxygenase ＝ cytochrome P450
arachidonic acid epoxygenase = CYP2J2 is an enzyme that produces epoxyeicosatrienoic acids by epoxidation of arachidonic acid. CYP2J2 mRNA is strongly expressed in the heart and weakly expressed in the liver, ileum, jejunum, large intestine, and kidney. It is thought that it plays an important role in the physiology of the heart in human heart via epoxyoxyicosatrienoic acids (Wu S, Moomaw CR, Tomer KB, Falck JR, Zeldin DC.M.
olecular cloning and expression of CYP2J2, a human
cytochrome P450 arachidonic acid epoxygenase high
ly expressed in heart. J Biol Chem 1996 Feb16; 271
(7): See 3460-8. ). Furthermore, CYP2J2 is present in the lung and
Bronchial smooth muscle contraction pressure via yeicosatrienoic acids
It regulates the ion permeability of airway epithelial cells and the contraction pressure of pulmonary blood vessels. It is also involved in the regulation of blood flow in central microvessels (Alkaye
d NJ, Birks EK, Hudetz AG, Roman RJ, Henderson L,
Harder DR. Inhibition of brainP-450 arachidonic ac
id epoxygenase decreases baseline cerebral blood f
low. Am J Physiol 1996 Oct; 271 (4 Pt 2): H1541-6. ). In the liver, arachidonic acid epoxygenase is involved in arachidonic acid metabolism and plays an important role in maintaining homeostasis (Rifkind AB, Lee C, Chang TK, Waxman DJ, Ara
chidonic acid metabolism by human cytochrome P450s
2C8, 2C9, 2E1, and 1A2: regioselectiveoxygenation
and evidence for a role for CYP2C enzymes in arac
hidonic acid epoxygenation in human liver microsom
es. Arch Biochem Biophys 1995 Jul 10; 320 (2): 380-9. ).

【００５１】以上から明らかな如く、ロイシンはアラキ
ドン酸の生理作用を抑制する。アミノ酸であることか
ら、長期投与が可能であり、慢性肝疾患における、微細
血管の血流改善や抗炎症作用による肝不全の改善や慢性
気管支炎の改善等が期待できる。As is clear from the above, leucine suppresses the physiological action of arachidonic acid. Since it is an amino acid, it can be administered for a long period of time, and in chronic liver disease, improvement of blood flow in microvessels, improvement of liver failure due to anti-inflammatory action, improvement of chronic bronchitis, etc. can be expected.

【００５２】先に述べたcytochrome P450 4F1に関して
アラキドン酸カスケードから考えてみる。Consider the cytochrome P450 4F1 described above from the arachidonic acid cascade.

【００５３】cytochrome P450 4F1 （CYP4F1）のヒトホ
モログはCYP4F14である。omega-hydroxylations of leu
kotriene B4, 6-trans-leukotriene B4, lipoxin A4, p
rostaglandin A1、及び8-HETEを有する幾つかのhydroxy
eicosatetraeonic acids (HETEs)を最も良く基質とし、
分解する。 lipoxin B4, laurate、及びarachidonateは
良い基質とならない。The human homolog of cytochrome P450 4F1 (CYP4F1) is CYP4F14. omega-hydroxylations of leu
kotriene B4, 6-trans-leukotriene B4, lipoxin A4, p
rostaglandin A1 and some hydroxy with 8-HETE
Using eicosatetraeonic acids (HETEs) as the best substrate,
Disassemble. Lipoxin B4, laurate, and arachidonate are not good substrates.

【００５４】leukotriene B4 (LTB4)は炎症のメディエ
ーターでありCYP4F14による代謝調節は重要である（Kik
uta Y, Kasyu H, Kusunose E, Kusunose M. 、Expressi
on and catalytic activity of mouse leukotriene B4
omega-hydroxylase, CYP4F14.Arch Biochem Biophys 20
00 Nov 15;383(2):225-32参照。）。LTB4の活性を抑制
して疾患の治療をする試みは数多く報告されている。例
えば、虚血再還流時の血管障害や筋肉障害の治療（Haya
shi S. 、Effects of LTB4 receptor antagonist on my
onephropathic metabolic syndrome: an experimental
study.、 Kurume Med J 2000;47(1):63-72参照。）、ク
ローン病等腸炎の治療（Fretland DJ, Anglin CP, Wido
mski D, Baron DA, Maziasz T, Smith PF. 、Pharmacol
ogical activity of the second generation leukotrie
ne B4 receptor antagonist, SC-53228: effects on ac
ute colonic inflammation and hepatic function in r
odents. Inflammation 1995 Oct;19(5):503-15参
照。）、関節炎治療（Kuwabara K, Yasui K, Jyoyama
H, Maruyama T, Fleisch JH, Hori Y. 、Effects of th
e second-generation leukotriene B(4) receptor anta
gonist, LY293111Na, on leukocyte infiltration and
collagen-induced arthritis in mice. Eur J Pharmaco
l 2000 Aug 25;402(3):275-85参照）、気管支炎治療（C
rooks SW, Bayley DL, Hill SL, Stockley RA. 、Bronc
hial inflammation in acute bacterial exacerbations
of chronic bronchitis: the role of leukotriene B
4.、 Eur Respir J 2000 Feb;15(2):274-80参照。）等
々。多くの炎症治療において、炎症メディエーターの制
御にロイシンが有効と思われる。Leukotriene B4 (LTB4) is a mediator of inflammation and metabolic regulation by CYP4F14 is important (Kik
uta Y, Kasyu H, Kusunose E, Kusunose M., Expressi
on and catalytic activity of mouse leukotriene B4
omega-hydroxylase, CYP4F14.Arch Biochem Biophys 20
See 00 Nov 15; 383 (2): 225-32. ). Many attempts to suppress the activity of LTB4 and treat the disease have been reported. For example, treatment of vascular disorders and muscle disorders during ischemia reperfusion (Haya
shi S., Effects of LTB4 receptor antagonist on my
onephropathic metabolic syndrome: an experimental
See study., Kurume Med J 2000; 47 (1): 63-72. ), Treatment of enteritis such as Crohn's disease (Fretland DJ, Anglin CP, Wido
mski D, Baron DA, Maziasz T, Smith PF., Pharmacol
ogical activity of the second generation leukotrie
ne B4 receptor antagonist, SC-53228: effects on ac
ute colonic inflammation and hepatic function in r
See odents. Inflammation 1995 Oct; 19 (5): 503-15. ), Arthritis treatment (Kuwabara K, Yasui K, Jyoyama
H, Maruyama T, Fleisch JH, Hori Y., Effects of th
e second-generation leukotriene B (4) receptor anta
gonist, LY293111Na, on leukocyte infiltration and
collagen-induced arthritis in mice. Eur J Pharmaco
l 2000 Aug 25; 402 (3): 275-85), Bronchitis treatment (C
rooks SW, Bayley DL, Hill SL, Stockley RA., Bronc
hial inflammation in acute bacterial exacerbations
of chronic bronchitis: the role of leukotriene B
4., Eur Respir J 2000 Feb; 15 (2): 274-80. )And so on. Leucine appears to be effective in controlling inflammatory mediators in many inflammatory treatments.

【００５５】V．各種臓器の機能維持剤 ロイシンは生体成分であり、強い生理作用を期待する医
薬には向いていない。生活習慣病、慢性疾患や発癌のよ
うに長期にわたって、少しずつ細胞・臓器が障害を受け
る場合がある。このような場合は、強くはないが、明ら
かな生理作用を持つアミノ酸を長期投与することによ
り、細胞・臓器の障害を減弱し、疾患の進行を遅らせた
り、初期の障害を回復したりする治療・予防法が有効と
思われる。V. Leucine, which is a function-maintaining agent for various organs, is a biological component and is not suitable for a drug that is expected to have a strong physiological action. There are cases where cells and organs are gradually damaged over a long period of time such as lifestyle-related diseases, chronic diseases and carcinogenesis. In such cases, long-term administration of amino acids, which are not strong but have clear physiological effects, attenuate the damage to cells and organs, delay the progression of the disease, and recover the initial damage.・ Preventive methods seem to be effective.

【００５６】先に述べたarachidonic acid epoxygenase
（CYP2J2）蛋白質はヒト及びラットの膵ランゲルハンス
島に発現している。epoxyeicosatrienoic acidsはラン
ゲルハンス島からインスリンやグルカゴンを分泌させる
働きがあり、CYP2J2はランゲルハンス島からのホルモン
分泌の制御に関与している可能性がある（Zeldin DC,Fo
ley J, Boyle JE, Moomaw CR, Tomer KB, Parker C, St
eenbergen C, Wu S.Predominant expression of an ara
chidonate epoxygenase in islets of Langerhans cell
s in human and rat pancreas. Endocrinology 1997 Ma
r;138(3):1338-46参照。）。ロイシンはCYP2J2発現亢進
作用を介して、膵臓からのインスリン・グルカゴン分泌
促進やインスリン・グルカゴン分泌機構の恒常性維持及
び臓機能の恒常性維持に貢献することが期待される。II
型糖尿病の原因は高血糖やインスリン抵抗性の継続から
膵臓のβ細胞の疲弊から死滅へ到ることによる。膵臓の
機能を維持することが糖尿病の進行を阻止することにな
る。Arachidonic acid epoxygenase described above
The (CYP2J2) protein is expressed in human and rat pancreatic islets of Langerhans. Epoxyeicosatrienoic acids have the function of secreting insulin and glucagon from Langerhans island, and CYP2J2 may be involved in the regulation of hormone secretion from Langerhans island (Zeldin DC, Fo
ley J, Boyle JE, Moomaw CR, Tomer KB, Parker C, St
eenbergen C, Wu S. Predominant expression of an ara
chidonate epoxygenase in islets of Langerhans cell
s in human and rat pancreas. Endocrinology 1997 Ma
See r; 138 (3): 1338-46. ). Leucine is expected to contribute to the promotion of insulin / glucagon secretion from the pancreas, the homeostasis of the insulin / glucagon secretory mechanism, and the homeostasis of visceral function through the action of enhancing CYP2J2 expression. II
The cause of type 2 diabetes is from hyperglycemia and continuation of insulin resistance to exhaustion of β cells in the pancreas to death. Maintaining the function of the pancreas blocks the progression of diabetes.

【００５７】また、先に述べたnucleobindinは神経細胞
の細胞質でカルシウムの恒常性維持を担っていると考え
られている（Taniguchi N, Taniura H, Niinobe M, Tak
ayama C, Tominaga-Yoshino K, Ogura A, Yoshikawa K.
、The postmitotic growthsuppressor necdin interac
ts with a calcium-binding protein (NEFA) in neuron
al cytoplasm.、 J Biol Chem 2000 Oct 13;275(41):31
674-81参照。）。ロイシンはNucleobindin発現亢進を介
して、神経細胞の機能維持することが考えられる。The nucleobindin described above is considered to be responsible for maintaining calcium homeostasis in the cytoplasm of nerve cells (Taniguchi N, Taniura H, Niinobe M, Tak.
ayama C, Tominaga-Yoshino K, Ogura A, Yoshikawa K.
, The postmitotic growthsuppressor necdin interac
ts with a calcium-binding protein (NEFA) in neuron
al cytoplasm., J Biol Chem 2000 Oct 13; 275 (41): 31.
See 674-81. ). Leucine is considered to maintain the function of nerve cells through the enhancement of Nucleobindin expression.

【００５８】ロイシンはacidic calponinの発現を亢進
する。acidic calponinは平滑筋と筋肉以外の組織で発
現し、サイトスケルトンと結合しているが、筋肉の収縮
とは関連しない（Maguchi, M.; Nishida, W.; Kohara,
K.; Kuwano, A.; Kondo, I.; Hiwada, K. : Molecular
cloning and gene mapping of human basic and acidic
calponins. Biochem. Biophys. Res. Commun. 217: 238
-244, 1995参照。）。神経系細胞において、acidic cal
poninは発生における神経細胞の成長や移動に関連した
収縮反応に関与していると推定されている（Ferhat L,
Charton G, Represa A, Ben-Ari Y, der Terrossian E,
Khrestchatisky M. 、Acidic calponincloned from ne
ural cells is differentially expressed during rat
brain development. Eur J Neurosci 1996 Jul;8(7):15
01-9参照。）。acidic calponinは脳の神経やグリア細
胞の過疎性に関与すると考えられる（Plantier M, Fatt
oum A, Menn B, Ben-Ari Y, Der Terrossian E, Repres
a A. Acidic calponin immunoreactivity in postnatal
rat brain and cultures: subcellular localization
in growth cones, under the plasma membrane and alo
ng actin and glialfilaments. Eur J Neurosci 1999 A
ug;11(8):2801-12参照。）。Leucine enhances the expression of acidic calponin. Acidic calponin is expressed in tissues other than smooth muscle and muscle and is associated with cytoskeleton, but is not associated with muscle contraction (Maguchi, M .; Nishida, W .; Kohara,
K .; Kuwano, A .; Kondo, I .; Hiwada, K .: Molecular
cloning and gene mapping of human basic and acidic
calponins. Biochem. Biophys. Res. Commun. 217: 238
See -244, 1995. ). In neural cells, acidic cal
It is presumed that ponin is involved in contractile responses related to growth and migration of nerve cells during development (Ferhat L,
Charton G, Represa A, Ben-Ari Y, der Terrossian E,
Khrestchatisky M., Acidic calponincloned from ne
ural cells is differentially expressed during rat
brain development. Eur J Neurosci 1996 Jul; 8 (7): 15
See 01-9. ). Acidic calponin is thought to be involved in the depopulation of nerves and glial cells in the brain (Plantier M, Fatt
oum A, Menn B, Ben-Ari Y, Der Terrossian E, Repres
a A. Acidic calponin immunoreactivity in postnatal
rat brain and cultures: subcellular localization
in growth cones, under the plasma membrane and alo
ng actin and glialfilaments.Eur J Neurosci 1999 A
See ug; 11 (8): 2801-12. ).

【００５９】acidic calponinはフラメント状アクチン
に結合するが一本鎖のアクチンには結合しない。おそら
くμclpainが制御するアクチンサイトスケルトンに関与
している（Yoshimoto R, Hori M, Ozaki H, Karaki H
、Proteolysis of acidic calponin by mu-calpain. J
Biochem (Tokyo) 2000 Dec;128(6):1045-9参照。）。Acidic calponin binds to fragment-like actin but not single-chain actin. Probably involved in actin site skeleton controlled by μclpain (Yoshimoto R, Hori M, Ozaki H, Karaki H
, Proteolysis of acidic calponin by mu-calpain. J
See Biochem (Tokyo) 2000 Dec; 128 (6): 1045-9. ).

【００６０】以上、acidic-calponinは平滑筋、神経、
肝臓等の恒常性維持に働いている。ロイシンはacidic-c
alponinの発現亢進を介してこれ等組織の恒常性維持に
役立つであろう。As described above, acidic-calponin is used for smooth muscle, nerve,
It works to maintain homeostasis in the liver. Leucine is acidic-c
It may help maintain homeostasis of these tissues through up-regulation of alponin.

【００６１】ロイシンはCarnitine palmitoyltransfera
se 1 alpha, liver isoformの発現を抑制する。この酵
素は、トリアシルグリセロールのアシルCoAとグリセロ
ールへの分解に関わる、脂肪分解の律速酵素である（細
胞機能と代謝マップ（日本生化学会編）、東京化学同
人、1997参照。）。よって、ロイシンの添加は肝細胞に
おいて脂肪分解を抑制すると考えられる。Leucine is Carnitine palmitoyltransfera
Inhibits the expression of se 1 alpha, liver isoform. This enzyme is a rate-limiting enzyme for lipolysis that is involved in the decomposition of triacylglycerol into acyl-CoA and glycerol (see Cellular Function and Metabolism Map (Edited by the Japanese Biochemical Society), Tokyo Kagaku Dojin, 1997). Therefore, addition of leucine is considered to suppress lipolysis in hepatocytes.

【００６２】また、mitochondrial long-chain 3-ketoa
cyl-CoA thiolase beta-subunitのmRNA発現が、ロイシ
ンにより上昇した。この酵素は別名enoyl-CoA hydratas
e, beta subunitとも呼ばれ、脂肪酸の脂肪鎖の延長反
応に関わる。ロイシンによるcarnitine palmitoyltrans
ferase I, alpha, liver formの発現抑制と連動して考
えると、ロイシンの投与は脂肪分解を抑制、即ち脂肪合
成の方向に働いていると考えられる。Also, mitochondrial long-chain 3-ketoa
Leucine increased the mRNA expression of cyl-CoA thiolase beta-subunit. This enzyme is also known as enoyl-CoA hydratas
Also called e, beta subunit, it is involved in the elongation reaction of fatty acid fatty chain. Carnitine palmitoyltrans by leucine
Considering in conjunction with the suppression of ferase I, alpha, and liver form expression, it is considered that the administration of leucine suppresses lipolysis, that is, works toward fat synthesis.

【００６３】血中の過剰遊離脂肪酸は色々の障害を引き
起こす。例えば、膵臓β細胞からのインスリン分泌に障
害を引き起こし、血糖の制御に障害を生じて、ひいては
糖尿病へ進展する（Lupi R, Del Guerra S, Fierabracc
i V, Marselli L, Novelli M, Patane G, Boggi U, Mos
ca F, Piro S, Del Prato S, Marchetti P. 、Lipotoxi
city in Human Pancreatic Islets and the Protective
Effect of Metformin. Diabetes 2002 Feb;51 Suppl
1:S134-S137参照。）。同様に血中過剰遊離脂肪酸は筋
肉等のインスリン抵抗性を引き起こし、糖尿病へ進行す
る（Bergman RN,Ader M. 、Free fatty acids and path
ogenesis of type 2 diabetes mellitus.Trends Endocr
inol Metab 2000 Nov;11(9):351-6参照。）。肝臓は遊
離脂肪酸を取り込みトリグリセリドを合成して、リポプ
ロテインと結合した状態で血中にもどし、これを各臓器
がエネルギー源として利用する。このように肝臓の脂質
代謝合成の調節は重要である。肝臓の脂質代謝合成機能
が不全となると、血中遊離脂肪酸の除去及び、全身への
脂肪の供給が障害される。Excess free fatty acids in blood cause various disorders. For example, insulin secretion from pancreatic β-cells is impaired, blood glucose control is impaired, and eventually diabetes is progressed (Lupi R, Del Guerra S, Fierabracc.
i V, Marselli L, Novelli M, Patane G, Boggi U, Mos
ca F, Piro S, Del Prato S, Marchetti P., Lipotoxi
city in Human Pancreatic Islets and the Protective
Effect of Metformin. Diabetes 2002 Feb; 51 Suppl
1: See S134-S137. ). Similarly, excessive free fatty acids in blood cause insulin resistance in muscles and progress to diabetes (Bergman RN, Ader M., Free fatty acids and path).
Generation of type 2 diabetes mellitus.Trends Endocr
See inol Metab 2000 Nov; 11 (9): 351-6. ). The liver takes in free fatty acids, synthesizes triglycerides, and returns them to the blood in the state of being bound to lipoproteins, which each organ uses as an energy source. Thus, regulation of hepatic lipid metabolism synthesis is important. When the hepatic lipid metabolism synthetic function is impaired, the removal of free fatty acids in blood and the supply of fat to the whole body are impaired.

【００６４】よってロイシンは肝臓の脂質代謝合成機能
の恒常性維持に貢献する。Therefore, leucine contributes to the homeostasis of the lipid metabolism and synthesis function of the liver.

【００６５】ロイシン投与はdelta 1-pyrroline-5-carb
oxylate synthetasの発現を亢進する。Leucine was administered delta 1-pyrroline-5-carb
Promotes the expression of oxylate synthetas.

【００６６】本酵素はオルニチンは尿素サイクルのメン
バーとして重要である。 尿素サイクルが低下してる疾
患、例えば肝硬変のような肝臓疾患において（Burton B
K.、Urea cycle disorders. Clin Liver Dis 2000 Nov;
4(4):815-30参照。）、ロイシン又はロイシンとグルタ
ミン酸等を投与し尿素サイクルを亢進することにより、
アンモニア血症を治療することが期待できる。特に、神
経系は高アンモニア血症で障害を受け易く、尿素サイク
ルの回復は重要な意味がある。In the present enzyme, ornithine is important as a member of the urea cycle. In diseases where the urea cycle is reduced, for example in liver diseases such as cirrhosis (Burton B
K., Urea cycle disorders. Clin Liver Dis 2000 Nov;
See 4 (4): 815-30. ), By administering leucine or leucine and glutamic acid and the like to enhance the urea cycle,
It can be expected to treat ammoniumemia. In particular, the nervous system is vulnerable to hyperammonemia, and recovery of the urea cycle has important meaning.

【００６７】VI．遺伝病治療薬 遺伝病は遺伝子の構造上の機能不全に起因するために、
遺伝子治療以外根本的治療は無い。しかし、現実には苦
しんでいる患者は存在する。遺伝子治療以外の方法で治
療する場合は、欠損する機能を補う薬物を一生投与し続
ける必要がある。アミノ酸は一生投与しても副作用が起
きないことが期待できる。アミノ酸の投与により少しで
も遺伝病の症状を軽減することができれば大きな福音で
ある。遺伝子の障害には色々の種類があり、それに対応
して症状も異なってくる。構造遺伝子に変異があり、活
性が低下している場合や、発現調節領域に変異があり、
刺激に対する応答が弱かったり、強かったりする場合が
ある。対象遺伝子の機能が完全に不全である場合は、ア
ミノ酸による発現誘導や抑制をかけても無効であるが、
遺伝子機能が一部残っている場合は、遺伝子発現誘導又
は抑制が症状を改善するであろう。VI. Genetic disease remedy Because genetic disease results from structural dysfunction of genes,
There is no radical treatment other than gene therapy. However, in reality there are patients suffering. When treating by a method other than gene therapy, it is necessary to continue administration of a drug that supplements the defective function throughout life. It is expected that amino acids will not cause side effects even after administration for a lifetime. It is a great gospel if amino acid administration can alleviate the symptoms of genetic diseases. There are various types of genetic disorders, and the symptoms vary accordingly. If there is a mutation in the structural gene and the activity is reduced, or there is a mutation in the expression control region
The response to the stimulus may be weak or strong. When the function of the target gene is completely defective, it is ineffective even if expression induction or suppression with amino acids is applied,
If some gene function remains, induction or repression of gene expression may ameliorate symptoms.

【００６８】先に述べたが、ロイシン投与は delta 1-p
yrroline-5-carboxylate synthetasの発現を亢進する。
delta 1-pyrroline-5-carboxylate synthetas(P5CS)は
ミトコンドリア内膜に存在し、ATP- やNADPH-依存性の,
bifunctional enzymeでglutamateを還元して Delta1-p
yrroline-5-carboxylateを生じる。Delta1-pyrroline-5
-carboxylateはプロリンやオルニチンをde novo合成す
るための必須の物質である（Hu CA, Lin WW, Obie C, V
alle D. ,Molecular enzymology of mammalianDelta1-p
yrroline-5-carboxylate synthase. Alternative splic
e donor utilization generates isoforms with differ
ent sensitivity to ornithine inhibition. J Biol Ch
em 1999 Mar 5;274(10):6754-62参照。）。P5CSの異常
による遺伝病が知られている。.神経破壊及び場合によ
り白内障、結締組織疾患等の症状が現われ、hyperammon
emia, hypoornithinemia, hypocitrullinemia, hypoarg
ininemia及びhypoprolinemiaを呈する（Baumgartner M
R, Hu CA, Almashanu S, Steel G, Obie C, Aral B, Ra
bier D, Kamoun P, Saudubray JM, Valle D. 、Hyperam
monemia with reduced ornithine, citrulline, argini
ne and proline: a new inborn error caused by a mut
ation in the gene encoding delta(1)-pyrroline-5-ca
rboxylate synthase. Hum Mol Genet 2000 Nov 22;9(1
9):2853-8参照。）。このような遺伝病の治療にロイシ
ンの長期投与が期待できる。As mentioned above, administration of leucine was carried out using delta 1-p
Enhances the expression of yrroline-5-carboxylate synthetas.
delta 1-pyrroline-5-carboxylate synthetas (P5CS) exists in the inner mitochondrial membrane and is ATP- and NADPH-dependent,
Delta1-p by reducing glutamate with bifunctional enzyme
This produces yrroline-5-carboxylate. Delta1-pyrroline-5
-carboxylate is an essential substance for de novo synthesis of proline and ornithine (Hu CA, Lin WW, Obie C, V
alle D., Molecular enzymology of mammalianDelta1-p
yrroline-5-carboxylate synthase. Alternative splic
e donor utilization generates isoforms with differ
ent sensitivity to ornithine inhibition. J Biol Ch
See em 1999 Mar 5; 274 (10): 6754-62. ). A genetic disease caused by an abnormality in P5CS is known. Symptoms such as nerve destruction and cataract, constrictive tissue disease may appear,
emia, hypoornithinemia, hypocitrullinemia, hypoarg
presents with ininemia and hypoprolinemia (Baumgartner M
R, Hu CA, Almashanu S, Steel G, Obie C, Aral B, Ra
bier D, Kamoun P, Saudubray JM, Valle D., Hyperam
monemia with reduced ornithine, citrulline, argini
ne and proline: a new inborn error caused by a mut
ation in the gene encoding delta (1) -pyrroline-5-ca
rboxylate synthase. Hum Mol Genet 2000 Nov 22; 9 (1
9): See 2853-8. ). Long-term administration of leucine can be expected for the treatment of such genetic diseases.

【００６９】本発明の薬剤を、例えば肝臓疾患治療又は
改善用に生体に投与する場合は、経口的に或いは直腸
内、皮下、髄腔内、筋肉内、静脈内、動脈内、経皮等の
非経口的に投与することができるが、好ましくは経口的
に或いは静脈内に投与するのがよい。When the drug of the present invention is administered to a living body for treating or ameliorating liver disease, it may be administered orally or rectally, subcutaneously, intrathecally, intramuscularly, intravenously, intraarterially, transdermally and the like. It can be administered parenterally, but it is preferably administered orally or intravenously.

【００７０】本発明によるロイシンを生体に投与する場
合、ロイシンは適当な剤型に製剤化して用いるのが好ま
しく、例えば錠剤、散剤、顆粒剤、細粒剤、丸剤、カプ
セル剤、トローチ剤、チュワブル剤、液剤、乳剤、懸濁
剤、坐剤、シロップ剤、ローション剤、軟膏剤、パップ
剤等の製剤で用いることができる。これ等の剤型に製剤
化するには薬学上許容しうる適当な担体、賦形剤、添加
剤等を用いて行うことができる。When the leucine according to the present invention is administered to a living body, it is preferable to formulate leucine into an appropriate dosage form and use it, for example, tablets, powders, granules, fine granules, pills, capsules, troches, It can be used in preparations such as chewable agents, solutions, emulsions, suspensions, suppositories, syrups, lotions, ointments and poultices. Formulation into these dosage forms can be carried out using suitable pharmaceutically acceptable carriers, excipients, additives and the like.

【００７１】本発明の薬剤を、例えば肝臓疾患の治療又
は改善用に静脈内投与する際に好ましい剤型は液剤であ
り、液剤を調製するには、例えば精製水、生理食塩水、
エタノール・プロピレングリコール・グリセリン・ポリ
エチレングリコール等のアルコール類、トリアセチン等
の溶媒を用いて行うことができる。このような製剤には
更に防腐剤、湿潤剤、乳化剤、分散剤、安定剤のような
補助剤を加えてもよい。また、懸濁剤として投与するこ
とも可能である。A preferred dosage form for intravenous administration of the agent of the present invention, for example, for treating or ameliorating liver diseases, is a liquid preparation. For preparing the liquid preparation, for example, purified water, physiological saline,
It can be carried out using an alcohol such as ethanol, propylene glycol, glycerin, polyethylene glycol, or a solvent such as triacetin. Auxiliary agents such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizers may be added to such preparations. It can also be administered as a suspension.

【００７２】また、錠剤、丸剤、散剤、顆粒剤、細粒
剤、トローチ剤、チュワブル剤等の固形製剤を調製する
には、例えば重炭酸ナトリウム、炭酸カルシウム、デン
プン、ショ糖、マンニトール、カルボキシメチルセルロ
ース等の担体、ステアリン酸カルシウム、ステアリン酸
マグネシウム、グリセリン等の添加剤を加えて常法によ
り行うことができる。また、セルロースアセテートフタ
レート、ヒドロキシプロピルメチルセルロースフタレー
ト、ポリビニルアルコールフタレート、スチレン−無水
マレイン酸共重合体、メタクリル酸−メタクリル酸メチ
ル共重合体等の腸溶性物質の有機溶媒あるいは水中溶液
を吹き付けて、腸溶性被膜を施して、腸溶性製剤として
製剤化することもできる。薬学上許容しうる担体には、
その他通常、必要により用いられる補助剤、芳香剤、安
定剤或いは防腐剤を含む。In order to prepare solid preparations such as tablets, pills, powders, granules, fine granules, troches and chewable preparations, for example, sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol, carboxy can be prepared. It can be carried out by an ordinary method by adding a carrier such as methyl cellulose and additives such as calcium stearate, magnesium stearate and glycerin. In addition, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, methacrylic acid-methyl methacrylate copolymer, etc., is sprayed with an organic solvent or water solution of an enteric substance to make it enteric-soluble. It is also possible to apply a coating and formulate it as an enteric coated preparation. Pharmaceutically acceptable carriers include
In addition, it usually contains auxiliary agents, fragrances, stabilizers or preservatives which are used as necessary.

【００７３】更に、本発明の薬剤を、例えば肝臓疾患等
の疾患治療又は改善に使用する場合は、高カロリー輸液
剤のような輸液製剤と併用して用いるか、ロイシンを他
の輸液製剤に添加して用いることもできる。When the drug of the present invention is used for treating or ameliorating diseases such as liver disease, it is used in combination with an infusion formulation such as a high calorie infusion, or leucine is added to another infusion formulation. It can also be used.

【００７４】本発明の薬剤を、例えば肝臓疾患治療又は
その改善用に使用する場合、飲食品又はその成分として
使用することもでき、例えば肝機能改善用食品としても
適用できる。この場合、既存の食品や飲料等にバリンを
直接添加して使用するか、或いはロイシンをガム、キャ
ンディー、ゼリー、グミ、クッキー、ビスケット、チョ
コレート等の菓子類、ジュース等の清涼飲料、チーズ、
バター、ヨーグルト等の乳製品、アイスクリーム、ハム
等の農産加工品、ちくわ、はんぺん等の水産加工品、そ
ば、うどん等の麺類、パン、ケーキ等の小麦粉加工品、
缶詰又は塩、こしょう、砂糖、人工甘味料等の調味食品
等に直接添加するか、またロイシンをこれ等の食品の加
工段階で混合し、加工することにより適用できる。肝機
能改善用の特定保健用医薬品としても応用可能である。
ロイシンを食品に添加・混合する際は、ロイシンを粉
末、顆粒、細粒等の固形状で用いるか、或いは液状のも
のを用いることができる。またロイシンを食品に加工す
る際は、通常の食品加工方法に基づき行うことができ
る。When the drug of the present invention is used for treating or ameliorating liver diseases, it can be used as a food or drink or an ingredient thereof, for example, as a food for improving liver function. In this case, it is used by directly adding valine to existing foods and beverages, or using leucine gum, candy, jelly, gummy, cookies, biscuits, confectionery such as chocolate, soft drinks such as juice, cheese, etc.
Dairy products such as butter and yogurt, processed agricultural products such as ice cream and ham, marine processed products such as chikuwa and rice, noodles such as buckwheat and udon, processed flour products such as bread and cake,
It can be applied by directly adding it to seasoned foods such as canned foods or salt, pepper, sugar, artificial sweeteners, etc., or by mixing and processing leucine at the processing stage of these foods. It can also be applied as a specified health drug for improving liver function.
When leucine is added to and mixed with foods, leucine can be used in solid form such as powder, granules, fine particles, or in liquid form. In addition, when leucine is processed into food, it can be carried out based on a usual food processing method.

【００７５】本発明の薬剤を、例えば肝臓疾患治療又は
その改善用組成物を医薬製剤として使用する場合には、
例えば肝臓疾患患者等に対して、その投与量は、患者の
性別、体型、体質、年齢、症状或いは投与剤型等により
異なるが、経口用製剤の場合一般にＬ−ロイシンを有効
成分として１日当り０．１〜３００ｇ、好ましくは１〜
１００ｇの範囲で適宜選択することができる。非経口投
与製剤の場合は上記経口投与（静脈注射等）の場合の１
日当たりの投与量に対して十〜二十分の一程度の上記有
効成分を使用することができる。When the agent of the present invention is used as a pharmaceutical preparation, for example, a composition for treating or ameliorating liver diseases,
For example, for patients with liver disease, the dose varies depending on the sex, body type, constitution, age, symptoms or dosage form of the patient, but in the case of an oral preparation, L-leucine is generally used as an active ingredient in an amount of 0 per day. .1 to 300 g, preferably 1 to
It can be appropriately selected within the range of 100 g. For parenteral preparations, 1 for the above oral administration (intravenous injection, etc.)
About 10 to 20 times as much of the above-mentioned active ingredient can be used per daily dose.

【００７６】投与回数は、患者の症状或いは投与剤型等
により異なるが、１日１〜数回が適当である。The frequency of administration varies depending on the patient's condition, dosage form, etc., but is preferably one to several times a day.

【００７７】[0077]

【実施例】以下に、実施例を挙げて本発明を更に詳細に
説明するが、本発明はこれ等に何ら限定されるものでは
ない。The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

【００７８】（実施例１）ロイシンにより特に発現が変動する遺伝子の同定 ＜細胞培養及びアミノ酸成分変更培地(RPMI-AA)＞Cell
line はH4IIEを使用し、10%ウシ胎児血清・ペニシリン
・ストレプトマイシン添加RPMI1640で継代培養した細胞
を用いた。実験時に作用させる培地は、RPMI1640をベー
スにアミノ酸を除きグルコース濃度を4.5g/Lに調製した
培地（以下RPMIAAと記す）を用いた。(Example 1) Identification of a gene whose expression is specifically changed by leucine <Cell culture and amino acid component change medium (RPMI-AA)> Cell
As the line, H4IIE was used, and cells subcultured with RPMI1640 supplemented with 10% fetal bovine serum / penicillin / streptomycin were used. As a medium to be used in the experiment, a medium (hereinafter, referred to as RPMIAA) was used, which was prepared by removing amino acids from RPMI1640 and adjusting the glucose concentration to 4.5 g / L.

【００７９】RPMIAA培地の調製は以下のように行った。
予め、4X Inorganic Salts Soln.と100X Vitamin Soln.
を以下のように調製して保存しておき、2段蒸留水にOth
er Componentと4X Inorganic Salts Soln.と100X Vitam
in Soln.を最終濃度が1Xになるように添加し、実験条件
により終濃度800μMのロイシンを添加した培地を用い
た。The RPMIAA medium was prepared as follows.
In advance, 4X Inorganic Salts Soln. And 100X Vitamin Soln.
Prepare as follows and store it in two-stage distilled water.
er Component and 4X Inorganic Salts Soln. and 100X Vitam
in Soln. was added so that the final concentration was 1X, and a medium to which leucine at a final concentration of 800 μM was added was used depending on the experimental conditions.

【００８０】5-1.4X RPMI base Medium ( glucose conc
entration :4.5 g/l ) AAの作成5-1.4X RPMI base Medium (glucose conc
entration: 4.5 g / l) Create AA

【００８１】 [0081]

【００８２】 [0082]

【００８３】 [0083]

【００８４】＜細胞への作用＞H4IIE細胞を10cm細胞培
養シャーレに80%Confluentになるまで培養し、Leucine
作用前日から16時間血清無添加のRPMI1640培地で培養
し、Leucine作用2時間前からRPMI-AA培地で培養を行っ
た。Leucine作用は、培地を800μM Leucineを含有したR
PMI-AA培地に交換することで作用を開始し、8時間の作
用を行った。コントロール用としてはRPMI-AA培地を8時
間作用させた。作用の終了は培地を急速に除去し、ISOG
EN（日本ジーン）1mLで細胞を溶解させることで行っ
た。実験はN=4で行った。<Action on cells> H4IIE cells were cultured in a 10 cm cell culture dish until they became 80% confluent, and Leucine was added.
The cells were cultured in RPMI1640 medium without serum for 16 hours from the day before the action, and were cultured in RPMI-AA medium 2 hours before the action of Leucine. Leucine action is the R medium containing 800 μM Leucine
The action was started by exchanging with PMI-AA medium, and the action was carried out for 8 hours. As a control, RPMI-AA medium was allowed to act for 8 hours. At the end of the action, the medium is rapidly removed and ISOG
It was performed by lysing cells with 1 mL of EN (Nippon Gene). The experiment was performed with N = 4.

【００８５】＜全RNAの精製＞10cmシャーレ1枚に対し、
1mlのISOGEN(日本ジーン)を加え、ホモジェナイズし
た。次に、200μlのクロロホルムを添加し、軽く撹拌し
た。室温に２分静置後、15000回転、4℃で10分間遠心分
離し、水層を回収した。水層にそれと等容量の２−プロ
パノールを加え、室温に5分静置後、15000回転、4℃で1
5分間遠心分離した。上清を捨て、沈澱したペレットに7
0％エタノールを加え、15000回転、4℃で15分間遠心分
離し、ペレットを回収した。ペレットを室温で5分間乾
燥させ、DEPC(ジエチルピロカーボネート)処理水を添加
し、ペレットを溶解させた。<Purification of total RNA> For one 10 cm dish,
1 ml of ISOGEN (Nippon Gene) was added and homogenized. Next, 200 μl of chloroform was added and stirred gently. After standing at room temperature for 2 minutes, the mixture was centrifuged at 15,000 rpm and 4 ° C. for 10 minutes to collect an aqueous layer. To the aqueous layer, add an equal volume of 2-propanol and leave it at room temperature for 5 minutes, then rotate at 15,000 rpm at 4 ° C for 1 minute.
Centrifuge for 5 minutes. Discard the supernatant and add 7 to the precipitated pellet.
0% ethanol was added, and the pellet was recovered by centrifugation at 15,000 rpm and 4 ° C for 15 minutes. The pellet was dried at room temperature for 5 minutes, and DEPC (diethylpyrocarbonate) -treated water was added to dissolve the pellet.

【００８６】上記の方法により、ロイシン処理群（１
群）、及びコントロール群（２群）の細胞からそれぞれ
全RNAを精製した。By the above method, the leucine treatment group (1
Total RNA was purified from cells of each group) and control group (two groups).

【００８７】＜テンプレートの合成＞Taqman PCRに用い
るテンプレートのcDNA合成はSuperScript First-Strand
Synthesis System for RT-PCR (GIBCO BRL社製)を使用
し、実施した。全RNA 500ng、0.5μg /μl Oligo (dT)
_12-18 1μl、10mM dNTP mix 1μlをDEPC処理水に溶解
し、全量を10μlとした。65℃で5分間反応後、氷冷し、
10×RT buffer 2μl、25mM MgCl2 4μl、0.1M DTT 2μ
l、RNase Inhibitor 1μlを加えて混合した後、42℃、2
分間保温し、逆転写酵素SUPERSCRIPT II RT 1μl (50
units)を添加した。42℃、50分間、更に70℃、15分間反
応させた。<Synthesis of Template> The cDNA synthesis of the template used for Taqman PCR is performed by SuperScript First-Strand.
It was performed using Synthesis System for RT-PCR (manufactured by GIBCO BRL). Total RNA 500ng, 0.5μg / μl Oligo (dT)
_12-18 1 μl and 10 mM dNTP mix 1 μl were dissolved in DEPC-treated water to make the total volume 10 μl. After reacting at 65 ℃ for 5 minutes, cool with ice,
10 × RT buffer 2μl, 25mM MgCl2 4μl, 0.1M DTT 2μ
l, RNase Inhibitor (1 μl) and mixed, then at 42 ℃, 2
Incubate for minutes and reverse transcriptase SUPERSCRIPT II RT 1 μl (50
units). The reaction was carried out at 42 ° C for 50 minutes, and further at 70 ° C for 15 minutes.

【００８８】＜プライマーの設計＞ミトコンドリアのTC
A回路及び電子伝達系にのATP産生に関与するタンパク質
についてプライマーを設計した。設計には外部データベ
ースPrimer3を用いた。( http://www-genome.wi.mit.ed
u/cgi-bin/primer/primer3_www.cgi)<Design of Primer> Mitochondrial TC
Primers were designed for proteins involved in ATP production in the A circuit and electron transfer system. An external database Primer3 was used for the design. (http: //www-genome.wi.mit.ed
u / cgi-bin / primer / primer3_www.cgi)

【００８９】下記表１に最終的にロイシン作用により変
動の見られた遺伝子の種類とハウスキーピング遺伝子で
あるβアクチン遺伝子におけるそのGenBank番号、UniGe
ne番号及び、プライマーの塩基配列を示す（配列表配列
番号１〜３０参照。）。In Table 1 below, the types of genes that were finally found to change by the action of leucine and their GenBank numbers in the β-actin gene, which is a housekeeping gene, and UniGe
The ne number and the base sequence of the primer are shown (see SEQ ID NOS: 1 to 30 in the sequence listing).

【００９０】[0090]

【表１】 [Table 1]

【００９１】Taqman PCR (SYBR Green法)反応 下記表２の組成の反応液をTaqman用PCRチューブ内で混
合し、ABI7700 Prism Sequence DetectorにおいてPCR反
応を行った。反応条件は以下の通り行った。Taqman PCR (SYBR Green method) reaction The reaction solutions having the compositions shown in Table 2 below were mixed in a Taqman PCR tube, and a PCR reaction was performed in an ABI7700 Prism Sequence Detector. The reaction conditions were as follows.

【００９２】反応条件：50℃2分→95℃10分→（95℃15
秒→60℃1分）を40サイクルReaction conditions: 50 ° C. 2 minutes → 95 ° C. 10 minutes → (95 ° C. 15 minutes
40 cycles of seconds → 60 ℃ 1 minute)

【００９３】[0093]

【表２】 [Table 2]

【００９４】＜データ解析＞Taqman PCR反応はN=4のRNA
サンプル1サンプルに対してN=3で行い、その蛍光値から
mRNAの相対量を求めた。その平均値を同サンプルで求め
たβアクチン遺伝子のmRNAの相対量で割ることで得られ
た値を比較した。この値の比が1.5倍以上開きのあった
遺伝子をリストアップした。<Data Analysis> Taqman PCR reaction was performed with N = 4 RNA.
Sample 1 sample was performed with N = 3, and from its fluorescence value
The relative amount of mRNA was determined. The values obtained by dividing the average value by the relative amount of mRNA of β-actin gene obtained in the same sample were compared. The genes whose ratios differed by 1.5 times or more were listed.

【００９５】＜結論＞発現上昇及び減少の見られた遺伝
子を以下にリストアップした（表３、表４参照。）。<Conclusion> Genes whose expression was increased or decreased were listed below (see Tables 3 and 4).

【００９６】これ等の遺伝子のmRNA量はLeucine作用8時
間後においてコントロール群（RPMI-AA８時間作用群）
に比べて1.5倍以上変動していることが示され、それぞ
れの疾患の治療や症状の改善にロイシンが有効であるこ
とが分かった。The amount of mRNA of these genes was controlled 8 hours after the Leucine action in the control group (RPMI-AA 8-hour action group).
It was found that leucine was effective in treating each disease and ameliorating the symptom, which was shown to be more than 1.5 times greater than that of.

【００９７】[0097]

【表３】ロイシンの作用で発現上昇する遺伝子 [Table 3] Genes whose expression is increased by the action of leucine

【００９８】[0098]

【表４】ロイシン作用で発現低下する遺伝子 [Table 4] Genes whose expression is reduced by the action of leucine

【００９９】[0099]

【発明の効果】本発明の薬剤によれば、従来の薬物治療
法よりも副作用が少なく、前記に説明したような各種の
疾患や合併症を引き起こす諸症状や異常等を改善、緩
和、回復等することができる優れた薬剤を提供すること
ができる。このように、本発明の薬剤を医薬品として使
用できるが、更に健機能性食品等飲食品として、或いは
飲食品に含まれる形態で使用することもできる。EFFECTS OF THE INVENTION The drug of the present invention has fewer side effects than conventional drug treatment methods, and improves, alleviates, recovers various symptoms and abnormalities causing various diseases and complications as described above. It is possible to provide an excellent drug that can be obtained. As described above, the drug of the present invention can be used as a drug, but can also be used as a food or drink such as a health-functional food, or in a form contained in the food or drink.

【０１００】従って、特に医薬品、食品等の分野におい
て広く本発明を使用することができ、故に本発明は工業
上極めて有用である。Therefore, the present invention can be widely used particularly in the fields of pharmaceuticals, foods, etc. Therefore, the present invention is industrially very useful.

【配列表】 SEQUENCE LISTING <110> Ajinomoto Co., Inc. <120> Medicines and Foods and Drinks for Treatment, Improvement or Prevention of Diseases <130> P7162AJ <140> <141> <160> 30 <170> PatentIn Ver. 2.1 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of ESTs, Highly similar to P5CS MOUSE DELTA 1-PYRROLINE-5-CARBOXYLATE SYNTHETASE <400> 1 atctccccgt ggatgtaggt 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of ESTs, Highly similar to P5CS MOUSE DELTA 1-PYRROLINE-5-CARBOXYLATE SYNTHETASE <400> 2 cagaagggga gactgggaat 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' Terminal of nucleobindin <400> 3 tgtttccatg gcaaaaatga 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' Terminal of nucleobindin <400> 4 tcctgtggca catacttcca 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of Glucose-6-phosphatase <400> 5 cttcggagtg acctttggag 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of Glucose-6-phosphatase <400> 6 ttgtttgctg gtgcttttgt 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of cytochrome P450 4F1 <400> 7 gccctccgta agattctggt 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of cytochrome P450 4F1 <400> 8 tgacctcaca gttggtctgg 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of aflatoxin B1 aldehyde reductase <400> 9 tcagccagct ctcactttga 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of aflatoxin B1 aldehyde reductase <400> 10 ggctcgatct gatctggttc 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of Androsterone UDP-glucuronosyltransferase <400> 11 cctcctctgg atgactgctg 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of Androsterone UDP-glucuronosyltransferase <400> 12 agcatctcaa gggaaaagca 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of mitochondrial long-chain 3-ketoacyl-CoA thiolase <400> 13 caagcagctg gcagtcatta 20 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of mitochondrial long-chain 3-ketoacyl-CoA thiolase <400> 14 gctttccgat aatcacagct tc 22 <210> 15 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of Liver activating protein <400> 15 aaaaacatca acagcaacaa cc 22 <210> 16 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of Liver activating protein <400> 16 gtgtggacac gggactgac 19 <210> 17 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of acidic calponin <400> 17 ttggcacaaa tgaagtctgc 20 <210> 18 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of acidic calponin <400> 18 tgacaaggtc tctcccgagt 20 <210> 19 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of arachidonic acid epoxygenase <400> 19 gacacactgc ctgtgtcctg 20 <210> 20 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of arachidonic acid epoxygenase <400> 20 ctgcctaggc cagaaacatc 20 <210> 21 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of ESTs, Highly similar to SYN_HUMAN ASPARAGINYL-TRNA SYNTHETASE <400> 21 aagctactac ccccaacagg a 21 <210> 22 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of ESTs, Highly similar to SYN_HUMAN ASPARAGINYL-TRNA SYNTHETASE <400> 22 ccctgaagca ggaaggaagt 20 <210> 23 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of Glycogen synthase 2 (liver) <400> 23 acacatgtcg gtggctacaa 20 <210> 24 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of Glycogen synthase 2 (liver) <400> 24 gtccatccct gatgcatacc 20 <210> 25 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of Carnitine palmitoyltransferase 1 alpha, liver isoform <400> 25 gtgagagccc actcttctgc 20 <210> 26 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of Carnitine palmitoyltransferase 1 alpha, liver isoform <400> 26 tgggacattc ctctctcagg 20 <210> 27 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of Alcohol dehydrogenase 3 (Adh3) <400> 27 gcagcttaac agggcagaag 20 <210> 28 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of Alcohol dehydrogenase 3 (Adh3) <400> 28 ccatccagga agttctccag 20 <210> 29 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5' terminal of cytoplasmic beta-actin <400> 29 ctccaagtat ccacggcata g 21 <210> 30 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3' terminal of cytoplasmic beta-actin <400> 30 aagcaatgct gtcaccttcc 20[Sequence list]                                SEQUENCE LISTING        <110> Ajinomoto Co., Inc. <120> Medicines and Foods and Drinks for Treatment,       Improvement or Prevention of Diseases <130> P7162AJ <140> <141> <160> 30 <170> PatentIn Ver. 2.1 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal       of ESTs, Highly similar to P5CS MOUSE DELTA       1-PYRROLINE-5-CARBOXYLATE SYNTHETASE <400> 1 atctccccgt ggatgtaggt 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       ESTs, Highly similar to P5CS MOUSE DELTA       1-PYRROLINE-5-CARBOXYLATE SYNTHETASE <400> 2 cagaagggga gactgggaat 20 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'Terminal of       nucleobindin <400> 3 tgtttccatg gcaaaaatga 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'Terminal of       nucleobindin <400> 4 tcctgtggca catacttcca 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       Glucose-6-phosphatase <400> 5 cttcggagtg acctttggag 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       Glucose-6-phosphatase <400> 6 ttgtttgctg gtgcttttgt 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       cytochrome P450 4F1 <400> 7 gccctccgta agattctggt 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       cytochrome P450 4F1 <400> 8 tgacctcaca gttggtctgg 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       aflatoxin B1 aldehyde reductase <400> 9 tcagccagct ctcactttga 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       aflatoxin B1 aldehyde reductase <400> 10 ggctcgatct gatctggttc 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       Androsterone UDP-glucuronosyltransferase <400> 11 cctcctctgg atgactgctg 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       Androsterone UDP-glucuronosyltransferase <400> 12 agcatctcaa gggaaaagca 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       mitochondrial long-chain 3-ketoacyl-CoA thiolase <400> 13 caagcagctg gcagtcatta 20 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       mitochondrial long-chain 3-ketoacyl-CoA thiolase <400> 14 gctttccgat aatcacagct tc 22 <210> 15 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       Liver activating protein <400> 15 aaaaacatca acagcaacaa cc 22 <210> 16 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       Liver activating protein <400> 16 gtgtggacac gggactgac 19 <210> 17 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       acidic calponin <400> 17 ttggcacaaa tgaagtctgc 20 <210> 18 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       acidic calponin <400> 18 tgacaaggtc tctcccgagt 20 <210> 19 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       arachidonic acid epoxygenase <400> 19 gacacactgc ctgtgtcctg 20 <210> 20 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       arachidonic acid epoxygenase <400> 20 ctgcctaggc cagaaacatc 20 <210> 21 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       ESTs, Highly similar to SYN_HUMAN ASPARAGINYL-TRNA       SYNTHETASE <400> 21 aagctactac ccccaacagg a 21 <210> 22 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       ESTs, Highly similar to SYN_HUMAN ASPARAGINYL-TRNA       SYNTHETASE <400> 22 ccctgaagca ggaaggaagt 20 <210> 23 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       Glycogen synthase 2 (liver) <400> 23 acacatgtcg gtggctacaa 20 <210> 24 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       Glycogen synthase 2 (liver) <400> 24 gtccatccct gatgcatacc 20 <210> 25 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       Carnitine palmitoyltransferase 1 alpha, liver       isoform <400> 25 gtgagagccc actcttctgc 20 <210> 26 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       Carnitine palmitoyltransferase 1 alpha, liver       isoform <400> 26 tgggacattc ctctctcagg 20 <210> 27 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       Alcohol dehydrogenase 3 (Adh3) <400> 27 gcagcttaac agggcagaag 20 <210> 28 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       Alcohol dehydrogenase 3 (Adh3) <400> 28 ccatccagga agttctccag 20 <210> 29 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 5'terminal of       cytoplasmic beta-actin <400> 29 ctccaagtat ccacggcata g 21 <210> 30 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: 3'terminal of       cytoplasmic beta-actin <400> 30 aagcaatgct gtcaccttcc 20

フロントページの続き (72)発明者 米澤 一仁 兵庫県神戸市東灘区向洋町中１−２−44 Ｆターム(参考） 4B018 LB01 LB02 LB03 LB06 LB07 LB08 LB09 LB10 MD19 4C206 AA01 AA02 FA53 MA04 MA37 MA72 MA75 MA86 NA14 ZA75 ZB26 ZC37 Continued front page    (72) Inventor Kazuhito Yonezawa             1-2-44 Naka, Koyo-cho, Higashinada-ku, Kobe, Hyogo F term (reference) 4B018 LB01 LB02 LB03 LB06 LB07                       LB08 LB09 LB10 MD19                 4C206 AA01 AA02 FA53 MA04 MA37                       MA72 MA75 MA86 NA14 ZA75                       ZB26 ZC37

Claims (8)

【特許請求の範囲】[Claims] 【請求項１】ロイシンを有効成分として含有することを
特徴とする下記薬剤の少なくとも一つに含まれる薬剤：
糖新生促進剤；薬剤の副作用軽減剤；発癌防止剤；肝再
生促進剤；アラキドン酸カスケード抑制剤；各種臓器の
機能改善及び／又は維持剤；並びに遺伝病治療薬。1. A drug contained in at least one of the following drugs, which comprises leucine as an active ingredient:
Gluconogenesis promoters; drug side-effect reducing agents; cancer carcinogenic agents; liver regeneration promoters; arachidonic acid cascade inhibitors; various organ function improving and / or maintaining agents; and genetic disease therapeutic agents. 【請求項２】医薬品又は飲食品の形態にある請求項１記
載の薬剤。2. The drug according to claim 1, which is in the form of a drug or food or drink. 【請求項３】ロイシンがＬ−ロイシンである請求項１又
は２記載の薬剤。3. The drug according to claim 1, wherein leucine is L-leucine. 【請求項４】飲食品が機能性食品である請求項２記載の
薬剤。4. The drug according to claim 2, wherein the food or drink is a functional food. 【請求項５】医薬品が非経口投与用である請求項２記載
の薬剤。5. The drug according to claim 2, which is for parenteral administration. 【請求項６】医薬品が輸液製剤である請求項５記載の薬
剤。6. The drug according to claim 5, wherein the drug is an infusion preparation. 【請求項７】医薬品が経口製剤である請求項２記載の薬
剤。7. The drug according to claim 2, wherein the drug is an oral preparation. 【請求項８】肝臓疾患、遺伝性疾患及び薬物中毒の何れ
か用である請求項１記載の薬剤。8. The drug according to claim 1, which is used for any of liver disease, genetic disease and drug addiction.