ROLE OF NADH--QUINONE REDUCTASE IN ETHANOL METABOLISM

过量急性酒精消费导致脂肪肝，并抑制 外源性物质的氧化和葡萄糖醛酸化，可能是通过 产生过量的NADH。 酚类食品添加剂的管理 抗氧化剂如BHA（丁基化羟基茴香醚）和BHT抑制了 乙醇诱导脂肪肝。 BHA通常代谢为 叔丁基醌（TBQ），也产生了显着增加的肝细胞色素， NADH：醌还原酶（QR）活性。 我们假设， 醌底物（TBQ）和酶的显着升高 由BHA给药引起的活性可抑制（乙醇 诱导）过量生产NADH，从而提高乙醇的速率 脂肪肝的发生与发展 葡萄糖醛酸化。 这将通过测定肝脏甘油三酯蓄积进行检测， NADH和NAD（乳酸/丙酮酸）的水平和比率，乙醇的速率 对乙酰氨基酚和羟基香豆素的氧化以及葡萄糖醛酸化 在小鼠和大鼠急性乙醇给药后。 我们将雇用;（a） 胞质NADH：醌还原酶的抑制剂（即，双香豆素），（B） 酶的诱导剂（即，BHA），以及（c）“耐战”（WR） 缺乏这种酶的老鼠品系。 我们还将使用3 不同的小鼠品系在它们的乙醇的基础速率 代谢以及他们的能力，以适应急性剂量的乙醇。 急性酒精性脂肪肝与体内脂质过氧化 （组织学、甘油三酯水平、乙烷生成）、 乙醇，酚类药物如扑热息痛的结合，以及 乳酸/丙酮酸（NADH/NAD）以及GSH/GSSG的比率将是 在这些条件下使用分离的肝细胞和 灌注的肝脏 通过使用分离的肝细胞和 这些动物的灌注肝脏将与从 完整的动物 因此，本研究将试图确定肝脏的核心作用， NADH：乙醇和异生物质中的醌还原酶（EC1.6.99.2） 新陈代谢. 清楚地了解这一生理功能 酶可以提供增强乙醇代谢以及 防止酒精滥用引起的脂肪肝。

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.