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Titolo:
ROLE OF FLAVIN-DEPENDENT MONOOXYGENASES AND CYTOCHROME-P450 ENZYMES IN THE SULFOXIDATION OF S-METHYL N,N-DIETHYLTHIOLCARBAMATE
Autore:
MADAN A; PARKINSON A; FAIMAN MD;
Indirizzi:
UNIV KANSAS,DEPT PHARMACOL & TOXICOL LAWRENCE KS 66045 UNIV KANSAS,DEPT PHARMACOL & TOXICOL LAWRENCE KS 66045 UNIV KANSAS,MED CTR,CTR ENVIRONM & OCCUPAT HLTH,DEPT PHARMACOL TOXICOL & THERAPEUT KANSAS CITY KS 66160
Titolo Testata:
Biochemical pharmacology
fascicolo: 12, volume: 46, anno: 1993,
pagine: 2291 - 2297
SICI:
0006-2952(1993)46:12<2291:ROFMAC>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
KM ALDEHYDE DEHYDROGENASE; CONTAINING MONO-OXYGENASE; MICROSOMAL CYTOCHROME-P-450; EPOXIDE HYDROLASE; LIVER; RAT; DISULFIRAM; ANTIBODIES; OXIDATION; THIOBENZAMIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
31
Recensione:
Indirizzi per estratti:
Citazione:
A. Madan et al., "ROLE OF FLAVIN-DEPENDENT MONOOXYGENASES AND CYTOCHROME-P450 ENZYMES IN THE SULFOXIDATION OF S-METHYL N,N-DIETHYLTHIOLCARBAMATE", Biochemical pharmacology, 46(12), 1993, pp. 2291-2297

Abstract

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 P450inhibitor 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 livermicrosomes from phenobarbital-treated rats. These results suggest that in male rat fiver 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.

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Documento generato il 28/09/20 alle ore 22:01:12