ROLE OF NADH--QUINONE REDUCTASE IN ETHANOL METABOLISM

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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.