Inhibition of the metabolism of ethyl carbamate by acetaldehyde.
Ethyl carbamate is an animal carcinogen when administered in large doses; it is naturally present in minute concentrations in fermented foods and beverages. Previous studies from this laboratory have demonstrated that ethanol, in vivo, inhibits the metabolism of ethyl carbamate in mice, but the enzyme system has not been identified. In an effort to further characterize the enzyme system responsible, the metabolic products of ethanol metabolism were studied to determine whether ethanol or either of its metabolites is inhibitory. Acetaldehyde (400 mg/kg) is a potent inhibitor of ethyl carbamate metabolism for about 2 hr in vitro, but sodium acetate is not. Paraldehyde (250 mg/kg) has a slower onset and longer duration of inhibition, suggesting that its conversion to acetaldehyde produces the inhibitory molecule. Disulfiram (200 mg/kg) has a prolonged inhibitory effect; this effect is enhanced and extended when the disulfiram is combined with acetaldehyde (400 mg/kg). D-Penicillamine, given in a regimen of 1.2 g/kg 0.5 hr before and 0.6 g/kg 1.5 and 3.5 hr after ethyl carbamate, is not inhibitory; however, it abolishes the inhibitory effect of acetaldehyde, presumably from sequestration of acetaldehyde. These studies demonstrate that acetaldehyde is an inhibitor of the metabolism of ethyl carbamate and suggest that acetaldehyde is one, and perhaps the only, molecule responsible for the inhibition seen when ethanol is administered to mice. In vitro incubation studies determined that ethyl carbamate was not metabolized by human plasma.
Kurata
N
N
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, KY 40292.
Kemper
R
R
Hurst
H E
HE
Waddell
W J
WJ
D000079:Acetaldehyde / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D010396:Penicillamine / Q000494:pharmacology; D014520:Urethane / Q000378:metabolism* / Q000493:pharmacokinetics
D002273:Carcinogens; D014520:Urethane; D000431:Ethanol; D010396:Penicillamine; D000079:Acetaldehyde; D004221:Disulfiram