title: Relationship between kinetics of liver alcohol dehydrogenase and alcohol metabolism.
abstract: Since alcohol dehydrogenase (ADH) catalyzes the rate-limiting step for ethanol metabolism, knowledge of the steady-state kinetics of ADH in liver is fundamental to the understanding of the pharmacokinetics of ethanol elimination. Accordingly, we have determined the kinetic properties of purified ADH isoenzymes in rat and human liver. At low ethanol concentrations, rat liver ADH obeys the Theorell-Chance mechanism and the equation predicts that activity in vivo is limited below Vmax mainly by NADH inhibition. At ethanol concentrations above 10 mM, substrate inhibition, consistent with the formation a dead-end ADH-NADH-ethanol complex, also becomes a rate-limiting factor. ADH activity, calculated from this equation and the concentrations of substrates and products present in liver during ethanol oxidation, agrees well with ethanol elimination rates measured in vivo. With human liver ADH, large differences are observed in the kinetic properties of 5 homodimeric isoenzymes: gamma 1 gamma 1 and gamma 2 gamma 2 exhibit negative cooperativity for ethanol saturation, while alpha alpha, beta 1 beta 1 and beta ind beta ind obey Michaelis-Menten kinetics. At pH 7.5, Km values for ethanol and Vmax values range 0.048 mM and 9 min-1 for beta 1 beta 1 to 64 mM and 560 min-1 for beta ind beta ind, respectively. Therefore, individuals with different ADH phenotypes should display different ethanol elimination profiles.
mesh_terms: D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D004592:Electrophoresis, Starch Gel; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008657:Metabolic Clearance Rate; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats
chemical_list: D007527:Isoenzymes; D009243:NAD; D000431:Ethanol; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase