The effects of disulfiram on equine hepatic alcohol dehydrogenase and its efficiency against alcoholism: vinegar effect.
The effects of disulfiram, its metabolite diethyldithiocarbamate and dithiodipyridine on alcohol metabolism of equine hepatic alcohol dehydrogenase (EC.1.1.1.1.) have been investigated. They were found to form enzyme-NAD(+)-inhibitor complexes which were competitive inhibitors of alcohol metabolism with dissociation constants (KEO,I) at pH 7.0 of 50 microM, 1.3 mM, and 260 microM, respectively. Acetate and vinegar behaved similarly in forming an inhibitory enzyme-NAD(+)-acetate ternary complex competitive with ethanol, with at pH 7.0 essentially identical dissociation constants of 4.0 mM and 3.8 mM, respectively. Disulfiram, diethyldithiocarbamate and dithiodipyridine were also found to exhibit affinity-labelling kinetics with liver alcohol dehydrogenase. The liver enzyme is chemically modified and inactivated in a similar manner by all three reagents via binary enzyme complexes with dissociation constants of 30 microM, 200 microM and 50 microM, respectively. Used as a protector against enzyme inactivation by DL-alpha-bromo-beta-(5-imidazolyl)-propionic acid, disulfiram, diethyl-dithiocarbamate and dithiodipyridine were found to form competitive binary enzyme complexes by binding to the active zinc site with KE,I values of 30 microM, 170 microM and 50 microM, respectively. The disulfiram and acetate binding to zinc results in the formation of binary and ternary complexes which inhibit alcohol metabolism at the enzyme level. Due to many unwanted side-effect), and the easy removal of its anti-drinking effects by drinking vinegar (vinegar effect), disulfiram may still be questioned as an effective drug against alcoholism.
Langeland
B T
BT
Institute of Biochemistry, University of Oslo, Norway.
McKinley-McKee
J S
JS
D000085:Acetates / Q000494:pharmacology*; D019342:Acetic Acid; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000818:Animals; D004221:Disulfiram / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics; D006736:Horses; D008099:Liver / Q000187:drug effects* / Q000201:enzymology
D000085:Acetates; D000427:Alcohol Deterrents; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019342:Acetic Acid; D004221:Disulfiram