S-methyl-N,N-diethylthiolcarbamate: a disulfiram metabolite and potent rat liver mitochondrial low Km aldehyde dehydrogenase inhibitor.
S-methyl-N,N-diethylthiolcarbamate-methyl ester (DETC-Me), a proposed disulfiram metabolite, was investigated both in vivo and in vitro for its effectiveness as a liver mitochondrial low Km aldehyde dehydrogenase (L Km ALDH) inhibitor. Male Sprague-Dawley rats were treated intraperitoneally with DETC-Me, killed at various times and L Km ALDH determined. DETC-Me was found to be a more potent in vivo inhibitor of L Km ALDH than either disulfiram, diethyldithiocarbamate (DDTC) or diethyldithiocarbamate-methyl ester (DDTC-Me). The ID50 for DETC-Me, DDTC-Me and disulfiram was 6.5, 15.5 and 56.2 mg/kg, respectively. The ID50 for DDTC was similar to DDTC-Me. Maximal inhibition of L Km ALDH occurred 30 minutes after DETC-Me administration. DETC-Me was ineffective as an in vitro inhibitor. DETC-Me produced a marked disulfiram-ethanol reaction (DER) at one-quarter of the dose of disulfiram or DDTC. Plasma DETC-Me in rats was greater after DETC-Me administration than after DDTC-Me, DDTC or disulfiram. In conclusion, DETC-Me is proposed to be a metabolite of disulfiram, and may be the immediate precursor of the chemical species responsible for L Km ALDH inhibition.
Hart
B W
BW
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Yourick
J J
JJ
Faiman
M D
MD
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D004221:Disulfiram / Q000378:metabolism / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology / Q000031:analogs & derivatives; D005260:Female; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology*; D051381:Rats; D011919:Rats, Inbred Strains
C016571:methyl diethyldithiocarbamate; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram