In vivo evaluation of ambivalent active-site-directed inactivators of liver alcohol dehydrogenase

In order to decrease the rate of ethanol metabolism for the treatment of acute and chronic alcoholism it would be useful to inhibit liver alcohol dehydrogenase in vivo. Based on a knowledge of the three-dimensional structure of the horse enzyme, we designed active-site-directed inactivators [p-(XCH2CONH)C6H4(CH2)3COHN2] which bind to the enzyme-NAD or enzyme-NADH complex and alkylate methionine residue 306. In vitro, these reagents inactivated mouse, rat, horse and human liver alcohol dehydrogenases faster in the presence than in the absence of NAD or NADH, but with slightly different specificity. Mice and rats pretreated with the reagents eliminated ethanol in blood more slowly than those not treated, and the specific activity of alcohol dehydrogenase in liver homogenates of treated animals was decreased. It appears that the design of active-site-directed reagents is feasible, but these reagents must be improved so that they are more efficacious in vivo.