GLUTATHIONE CARBAMOYLATION WITH S-METHYL N,N-DIETHYLTHIOLCARBAMATE SULFOXIDE AND SULFONE - MITOCHONDRIAL LOW K-M ALDEHYDE DEHYDROGENASE INHIBITION AND IMPLICATIONS FOR ITS ALCOHOL-DETERRENT ACTION

S-Methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) and sulfone ( DETC-MeSO2) both inhibit rat liver low K-m aldehyde dehydrogenase (ALD H(2)) in vitro and in vivo (Nagendra et al., Biochem Pharmacol 47: 146 5-1467, 1994). DETC-MeSO has been shown to be a metabolite of disulfir am, but DETC-MeSO2 has not. Studies were carried out to further invest igate the inhibition of ALDH(2) by DETC-MeSO and DETC-MeSO2. In an in vitro system containing hydrogen peroxide and horseradish peroxidase, the rate of DETC-MeSO oxidation corresponded to the rate of DETC-MeSO2 formation. Carbamoylation of GSH by both DETC-MeSO and DETC-MeSO2 was observed in a rat liver S-9 fraction. Carbamoylation of GSH was not o bserved in the presence of N-methylmaleimide. In in vitro studies, DET C-MeSO and DETC-MeSO2 were equipotent ALDH(2) inhibitors when solubili zed mitochondria were used, but DETC-MeSO was approximately four times more potent than DETC-MeSO2 in intact mitochondria. In studies with r ats, the dose (i.p. or oral) required to inhibit 50% ALDH(2) (ED50) wa s 3.5 mg/kg for DETC-MeSO and approximately 35 mg/kg for DETC-MeSO2, a pproximately a 10-fold difference. Furthermore, maximum ALDH(2) inhibi tion occurred 1 hr after DETC-MeSO administration, whereas maximal ALD H(2) inhibition occurred 8 hr after DETC-MeSO2 dosing. DETC-MeSO is, t herefore, not only a more potent ALDH(2) inhibitor than DETC-MeSO2 in vivo, but also in vitro when intact mitochondria are utilized. The in vitro results thus support the in vivo findings. Since oxidation of DE TC-MeSO can occur both enzymatically and non-enzymatically, it is poss ible that DETC-MeSO2 is formed in vivo. DETC-MeSO2, however, is not as effective as DETC-MeSO in inhibiting ALDH(2), probably because it has difficulty penetrating the mitochondrial membrane. Thus, even if DETC -MeSO2 is formed in vivo from DETC-MeSO, it is the metabolite DETC-MeS O that is most likely responsible for the inhibition of ALDH(2) after disulfiram administration. (C) 1998 Elsevier Science Inc.