Diethyldithiocarbamate methyl ester sulfoxide, an inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase and putative metabolite of disulfiram.
S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) is a potent inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2) both in vivo and in vitro, and has been proposed to be the metabolite responsible for ALDH2 inhibition by disulfiram. Diethyldithiocarbamate methyl ester (DDTC-Me), a key intermediate in the metabolism of disulfiram, has been shown to be bioactivated by microsomal monooxygenases to diethyldithiocarbamate methyl ester sulfoxide (DDTC-Me sulfoxide). Studies were conducted to determine if DDTC-Me sulfoxide was also an active metabolite of disulfiram and inhibitor of ALDH2. DDTC-Me sulfoxide inhibited ALDH2 in vitro with an IC50 of 10 microM, and in vivo with an ID50 of 31 mg/kg (170 mumol/kg). Maximal ALDH2 inhibition in vivo was observed 8 hr after the administration of 45.2 mg/kg DDTC-Me sulfoxide, with ALDH2 activity returning to control levels after 48 hr. Although DDTC-Me sulfoxide inhibited ALDH2 in vivo, DDTC-Me sulfoxide was not detected in plasma from rats treated with either disulfiram (75 mg/kg), DDTC-Me (122.25 mg/kg), or DDTC-Me sulfoxide (45.2 mg/kg). However, DDTC-Me and S-methyl N,N-diethylthiolcarbamate (DETC-Me) were detected in plasma from rats treated with DDTC-Me sulfoxide. In rats treated with DDTC-Me sulfoxide and challenged with ethanol, a small increase of approximately microM in blood acetaldhyde and an inconsistent drop in blood pressure was observed. In conclusion, DDTC-Me sulfoxide inhibited ALDH2 in vitro and in vivo, was less potent than DETC- MeSO, and was not detected after disulfiram administration.
Madan
A
A
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Faiman
M D
MD
D000079:Acetaldehyde / Q000493:pharmacokinetics; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004221:Disulfiram / Q000493:pharmacokinetics*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000431:Ethanol / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
C073220:S-methyl N,N-diethylthiolcarbamate sulfoxide; D000431:Ethanol; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D004221:Disulfiram