Role of flavin-dependent monooxygenases and cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate

Biochem Pharmacol. 1993 Dec 14;46(12):2291-7. doi: 10.1016/0006-2952(93)90620-c.


Disulfiram is bioactivated to S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), the metabolite proposed to be responsible for the action of disulfiram as an aldehyde dehydrogenase inhibitor. This bioactivation process includes a reduction, an S-methylation, and two successive oxidations. Sulfur-containing functional groups are substrates for cytochrome P450 enzymes or flavin-containing monooxygenases (FMO). In the present study, we investigated the contribution of these monooxygenases to the formation of DETC-MeSO from its immediate precursor S-methyl N,N-diethylthiolcarbamate (DETC-Me). Liver microsomes obtained from mature male rats were incubated with DETC-Me. The formation of DETC-MeSO was blocked completely by solubilization of the microsomes with the detergent Emulgen 911, or by the presence of the cytochrome P450 inhibitor 1-benzylimidazole. However, thermal-inactivation of FMO resulted in only a partial loss in DETC-MeSO formation. Liver microsomes from phenobarbital-treated rats showed a 4- to 5-fold increase in the rate of formation of DETC-MeSO, compared with controls. Liver microsomes from pyrazole-treated rats showed a 50% decrease in the sulfoxidation of DETC-Me compared with controls. In a purified reconstituted system, cytochrome P450 2B1 (CYP2B1) catalyzed the formation of DETC-MeSO at a rate of 51 nmol DETC-MeSO formed/min/nmol cytochrome P450. Antibodies to CYP2B1 caused a 60% inhibition of DETC-MeSO formation by liver microsomes from phenobarbital-treated rats. These results suggest that in male rat liver microsomes, cytochrome P450 plays a major role in catalyzing the sulfoxidation of DETC-Me, whereas FMO plays a minor role (< 10%). Also, in liver microsomes from phenobarbital-treated rats, CYP2B1 is the major catalyst for the sulfoxidation of DETC-Me.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies
  • Biotransformation
  • Cytochrome P-450 Enzyme System / metabolism*
  • Disulfiram / pharmacokinetics
  • Ditiocarb / analogs & derivatives
  • Ditiocarb / metabolism
  • Male
  • Microsomes, Liver / metabolism
  • Oxygenases / antagonists & inhibitors
  • Oxygenases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sulfoxides / metabolism*
  • Thiocarbamates / metabolism*


  • Antibodies
  • Sulfoxides
  • Thiocarbamates
  • S-methyl N,N-diethylthiolcarbamate sulfoxide
  • S-methyl diethylthiocarbamate
  • Cytochrome P-450 Enzyme System
  • Ditiocarb
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)
  • Disulfiram