Degradation of aliphatic alcohols by human liver alcohol dehydrogenase: effect of ethanol and pharmacokinetic implications.
We have investigated the oxidation of low molecular weight aliphatic alcohols by Class I, II, and III alcohol dehydrogenases (ADH) isolated from human liver. These alcohols are generally present as byproducts of alcoholic beverages and referred to as alcoholic congeners. At concentrations corresponding to those in the blood after ingestion of alcoholic drinks (10-100 microM), the oxidation of propanol-1, isobutanol, 2-methylbutanol-1, and 3-methylbutanol-1 was mediated mainly by the isoenzymes of class I ADH, whereas butanol-1 was metabolized by Class I and II ADH. Class II ADH showed no activity with any of the alcohols at concentrations up to 100 microM. Lineweaver-Burk plots of the Class I ADH-catalyzed oxidation of all the congeners tested were linear in the pharmacokinetically relevant concentration range between 10 and 100 microM. Ethanol at concentrations found in the blood after moderate drinking (2.5-10 mM) caused a concentration-dependent inhibition of the congener oxidation. The experimentally determined kinetic constants were used to simulate the pharmacokinetics of propanol-1 metabolism in a multicompartment model system which accounts for first-pass elimination. The results suggest, in agreement with reported data from drinking experiments, that congener alcohols undergo considerable metabolism during the first liver passage, the extent of the first-pass metabolism depending on the ethanol dose.