ROLE OF NADH--QUINONE REDUCTASE IN ETHANOL METABOLISM

NADH--醌还原酶在乙醇代谢中的作用

• 批准号: 3109292
• 负责人: ROBERT J. RUBIN
• 金额: $ 12.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3109292
• 关键词: acetaminophen; alcoholic beverage consumption; alcoholic fatty liver; alcoholism /alcohol abuse; antioxidants; benzene; butylated hydroxytoluene; catalase; enzyme induction /repression; ethanol; ethers; fluorimetry; gas chromatography; genetic strain; glucuronides; glutathione; histology; hydrogen peroxide; isolation perfusion; lipid peroxides; liver cells; liver metabolism; menadione; nicotinamide adenine dinucleotide; oxidoreductase inhibitor; tissue /cell culture; triglycerides

Excessive acute consumption of ethanol causes fatty liver, and inhibits both the oxidation and the glucuronidation of xenobiotics, perhaps by producing excess NADH. Administration of phenolic food additive antioxidants such as BHA (butylated hydroxyanisole) and BHT inhibits the induction of fatty liver by ethanol. BHA is normally metabolized to t-butylquinone (TBQ) and also produces a marked increase of hepatic cytosoe NADH:quinone reductase (QR) activity. We postulate that both the provision of the quinone substrate (TBQ) and the marked elevation of the enzyme activity resulting from the BHA administration may inhibit the (ethanol induced) excessive production of NADH, thus enhancing the rate of ethanol metabolism and preventing the induction of fatty liver and the suppression of glucuronidation. This will be tested by determining the hepatic triglyceride accumulation, level and ratios of NADH and NAD (lactate/pyruvate), rates of ethanol oxidation as well as the glucuronidation of paracetamol and hydroxycoumarin in mice and rats upon acute ethanol administration. We will employ; (a) the inhibitor of cytosolic NADH:quinone reductase (i.e., dicoumarol), (b) inducer of the enzyme (i.e., BHA), and (c) the "Warfarin Resistant" (WR) strain of rats which are deficient in the enzyme. We will also use 3 different mouse strains which differ in both their basal rate of ethanol metabolism as well as in their ability to adapt to acute doses of ethanol. The acute ethanol induced fatty liver and lipid peroxidation in vivo (histology, triglyceride levels, ethane generation), rates for oxidation of ethanol, conjugation of a phenolic drug-like paracetamol, and the levels and ratios of lactate/pyruvate (NADH/NAD) as well as GSH/GSSG will be determined under these conditions using both the isolated hepatocytes and perfused livers. Results obtained by using isolated hepatocytes and perfused livers of these animals will be correlated to those obtained from intact animals. Therefore, this study will attempt to establish the central role of hepatic NADH: quinone reductase (EC 1.6.99.2) both in ethanol and xenobiotic metabolism. Clear understanding of the physiological function of this enzyme may provide means to enhance the metabolism of ethanol as well as to protect against the fatty liver induced by ethanol abuse.

过量急性饮用乙醇会引起脂肪肝，并抑制

项目成果

Induction of physical dependence by chronic alcohol treatment and enhancement of hepatic metabolism of 7-ethoxycoumarin and subsequent conjugation of its metabolite in perfused rat livers.

通过长期酒精治疗诱导身体依赖性，增强 7-乙氧基香豆素的肝脏代谢及其随后在灌注大鼠肝脏中的代谢物的结合。

• 发表时间: 1987
• 期刊: Archives internationales de pharmacodynamie et de therapie
• 作者: Hong,SS;Roh,HK;Dong,MS;Cha,YN
• 通讯作者: Cha,YN

Functional relationship between initial oxidation of 7-ethoxycoumarin and subsequent conjugation of 7-hydroxycoumarin in isolated perfused rat livers.

离体灌注大鼠肝脏中 7-乙氧基香豆素的初始氧化与随后的 7-羟基香豆素结合之间的功能关系。

• DOI: 10.1016/0009-2797(87)90034-2
• 发表时间: 1987
• 期刊: Chemico-biological interactions
• 影响因子: 5.1
• 作者: Cha,YN;Dong,MS;Hong,SS
• 通讯作者: Hong,SS

Role of quinone reductase in in vivo ethanol metabolism and toxicity.

醌还原酶在体内乙醇代谢和毒性中的作用。

• DOI: 10.1006/taap.1994.1015
• 发表时间: 1994
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Chung,JH;Cha,YN;Rubin,RJ
• 通讯作者: Rubin,RJ