Bioactivation of S-methyl N,N-diethylthiolcarbamate to S-methyl N,N-diethylthiolcarbamate sulfoxide. Implications for the role of cytochrome P450.
Diethyldithiocarbamate (DDTC), diethyldithiocarbamate methyl ester (DDTC-Me), S-methyl N,N-diethylthiolcarbamate (DETC-Me) and S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) are all metabolites of disulfiram. All inhibit rat liver low Km aldehyde dehydrogenase (ALDH) in vivo, with the order of potency being DETC-MeSO > DETC-Me > DDTC-Me > DDTC. Studies were carried out both in vivo and in vitro to further investigate the role of bioactivation as a requirement for the action of disulfiram as a liver ALDH inhibitor. The cytochrome P450 inhibitor 1-benzylimidazole (NBI) was employed as a pharmacological tool to study the metabolism of DETC-Me to DETC-MeSO. Administration of NBI to rats prior to DETC-Me treatment blocked the inhibition of liver mitochondrial low Km ALDH by DETC-Me. This was accompanied by an increase in plasma DETC-ME and a decrease in plasma DETC-MeSO. Pretreatment of rats with NBI prior to DETC-MeSO administration did not block the inhibition of liver mitochondrial low Km ALDH by DETC-MeSO. In in vitro studies, the inclusion of NBI in an incubation containing rat liver microsomes, mitochondria and an NADPH-generating system blocked the formation of DETC-MeSO and inhibition of liver mitochondrial low Km ALDH by DETC-Me. DETC-MeSO was found to be a potent inhibitor of rat liver mitochondrial low Km ALDH both in vivo and in vitro. The data suggest that the metabolism of DETC-Me to DETC-MeSO is mediated by cytochrome P450, and that inhibition of cytochrome P450 by inhibitors such as NBI block the inhibition of low Km ALDH by DETC-Me.
Hart
B W
BW
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Faiman
M D
MD
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004050:Ditiocarb / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000493:pharmacokinetics*
D013859:Thiocarbamates; C073220:S-methyl N,N-diethylthiolcarbamate sulfoxide; C070631:S-methyl diethylthiocarbamate; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D000444:Aldehyde Dehydrogenase