Characterization of diethyldithiocarbamate methyl ester sulfine as an intermediate in the bioactivation of disulfiram.
Disulfiram is bioactivated through a series of intermediates, ultimately forming S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the metabolite proposed to be responsible for the in vivo inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2). Diethyldithiocarbamate methyl ester sulfine (DDTC-Me sulfine) also has been recently identified as a possible metabolite of disulfiram (Madan and Faiman, 1994). In the present studies, DDTC-Me sulfine was characterized and was found to inhibit ALDH2 in vivo (ID50 = 57 mumol/kg) but not in vitro. Maximum inhibition of ALDH2 in rats was observed 1 hr after the i.p. administration of DDTC-Me sulfine. Pretreatment of rats with 1-benzylimidazole, a cytochrome P450 inhibitor, blocked the DDTC-Me sulfine-mediated inhibition of ALDH2. This suggested that DDTC-Me sulfine was further bioactivated by a cytochrome P450-dependent mechanism. DDTC-Me sulfine could not be detected in rat plasma after the i.p. administration of disulfiram (75 mg/kg), DDTC-Me (122 mg/kg) or DDTC-Me sulfine (22.6 mg/kg). However, S-methyl N,N-diethylthiolcarbamate (DETC-Me), the desulfurated form of DDTC-Me, was detected as a major metabolite of DDTC-Me sulfine in rat plasma after DDTC-Me sulfine administration. Also, a disulfiram-like-ethanol reaction was observed in rats treated with DDTC-Me sulfine and challenged with ethanol. These data provided additional support for the idea that DDTC-Me sulfine is an intermediate formed after DDTC-Me metabolism and is probably a precursor to DETC-Me in the overall bioactivation of disulfiram to DETC-Me sulfoxide.
Department of Pharmacology and Toxicology, University of Kansas, Lawrence.
A
A
Madan
M D
MD
Faiman
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D004221:Disulfiram / Q000493:pharmacokinetics*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013454:Sulfoxides / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; D013454:Sulfoxides; D000431:Ethanol; C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram