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Diethyldithiocarbamate Methyl Ester Sulfoxide, an Inhibitor of Rat Liver Mitochondrial Low K m Aldehyde Dehydrogenase and Putative Metabolite of Disulfiram
Author(s) -
Madan Ajay,
Faiman Morris D.
Publication year - 1994
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1994.tb00075.x
Subject(s) - disulfiram , chemistry , aldehyde dehydrogenase , in vivo , dimethyl sulfoxide , metabolite , sulfoxide , aldh2 , pharmacology , acetaldehyde , biochemistry , active metabolite , stereochemistry , ethanol , enzyme , organic chemistry , biology , microbiology and biotechnology
S‐methyl N,N ‐diethylthiolcarbamate sulfoxide (DETC‐MeSO) is a potent inhibitor of rat liver mitochondrial low K m aldehyde dehydrogenase (ALDH 2 ) both in vivo and in vitro, and has been proposed to be the metabolite responsible for ALDH 2 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 ALDH 2 . DDTC‐Me sulfoxide inhibited ALDH 2 in vitro with an IC 50 of 10 μm, and in vivo with an ID 50 of 31 mg/kg (170 μmol/kg). Maximal ALDH 2 inhibition in vivo was observed 8 hr after the administration of 45.2 mg/kg DDTC‐Me sulfoxide, with ALDH 2 activity returning to control levels after 48 hr. Although DDTC‐Me sulfoxide inhibited ALDH 2 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 ALDH 2 in vitro and in vivo, was less potent than DETC‐ MeSO, and was not detected after disulfiram administration.