Diethyldithiocarbamate Methyl Ester Sulfoxide, an Inhibitor of Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase and Putative Metabolite of Disulfiram |
| |
Authors: | Ajay Madan Morris D. Faiman |
| |
Affiliation: | Department of Pharmacology and Toxicology, the University of Kansas, Lawrence, Kansas. |
| |
Abstract: | S-methyl N,N -diethylthiolcarbamate sulfoxide (DETC-MeSO) is a potent inhibitor of rat liver mitochondrial low K m 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 μm, and in vivo with an ID50 of 31 mg/kg (170 μmol/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 ∼9 μm in blood acetaldehyde 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. |
| |
Keywords: | Disulfiram Aldehyde dehydrogenase Diethyldithiocarbamate methyl ester sulfoxide S-methyl N,N-diethylthiolcarbamate sulfoxide Alcoholism |
|
|