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Titolo:
IDENTIFICATION OF THE HUMAN AND RAT P450 ENZYMES RESPONSIBLE FOR THE SULFOXIDATION OF S-METHYL N,N-DIETHYLTHIOLCARBAMATE (DETC-ME) - THE TERMINAL STEP IN THE BIOACTIVATION OF DISULFIRAM
Autore:
MADAN A; PARKINSON A; FAIMAN MD;
Indirizzi:
UNIV KANSAS,DEPT PHARMACOL LAWRENCE KS 66045 UNIV KANSAS,DEPT PHARMACOL & TOXICOL LAWRENCE KS 66045 UNIV KANSAS,MED CTR,CTR ENVIRONM & OCCUPAT HLTH,DEPT PHARMACOL TOXICOL & THERAPEUT LAWRENCE KS 66045
Titolo Testata:
Drug metabolism and disposition
fascicolo: 10, volume: 23, anno: 1995,
pagine: 1153 - 1162
SICI:
0090-9556(1995)23:10<1153:IOTHAR>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
LIVER MICROSOMAL CYTOCHROME-P-450; KM ALDEHYDE DEHYDROGENASE; TESTOSTERONE OXIDATION; SPECIES-DIFFERENCES; EPOXIDE HYDROLASE; METABOLISM; HYDROXYLATION; INHIBITION; FORMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
44
Recensione:
Indirizzi per estratti:
Citazione:
A. Madan et al., "IDENTIFICATION OF THE HUMAN AND RAT P450 ENZYMES RESPONSIBLE FOR THE SULFOXIDATION OF S-METHYL N,N-DIETHYLTHIOLCARBAMATE (DETC-ME) - THE TERMINAL STEP IN THE BIOACTIVATION OF DISULFIRAM", Drug metabolism and disposition, 23(10), 1995, pp. 1153-1162

Abstract

The present study investigated the role of rat and human cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate(DETC-Me) to S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the putative active metabolite of disulfiram, DETC-Me sulfoxidation by microsomes from male and female rats treated with various cytochrome P450-enzyme inducers suggested that multiple enzymes can catalyze this reaction, and these include, CYP1A1/2, CYP2B1/2, and CYP3A1/2, All cDNA-expressed human cytochrome P450 enzymes examined catalyzed the sulfoxidation of DETC-Me, The turnover rates (min(-1)) of DETC-Me sulfoxidation by the cDNA-expressed cytochrome P450 enzymes ranked as follows: CYP3A4 > CYP2A6 = CYP2C9 > CYP1A2 > CYP2B6 = CYP2E1 > CYP1A1 > CYP2D6. Interestingly, CYP3A4 ranked first or last, depending on whether or not additional NADPH-cytochrome P450 reductase was coexpressed in the lymphoblastoid cells. This complicated estimates of the contribution of CYP3A4 to DETC-Me sulfoxidation by human liver microsomes,The sample-to-sample variation in DETC-Me sulfoxidation by a bank of human liver microsomes (N = 13) correlated highly with coumarin 7-hydroxylation (r = 0.88) and testosterone 6 beta-hydroxylation (r = 0.90),suggesting that CYP2A6 and CYP3A4/5 contribute to the sulfoxidation of DETC-Me by human liver microsomes, Although, chlorzoxazone 6-hydroxylation (a marker for CYP2E1) correlated poorly with DETC-Me sulfoxidation, the correlation improved from r = 0.07 to r = 0.44 when DETC-Me sulfoxidation was studied in the presence of the CYP2A6 inhibitor, coumarin, Similarly, when DETC-Me sulfoxidation was studied in the presence of diethyldithiocarbamate (DDTC), the inhibited DETC-Me sulfoxidase activity correlated better (r = 0.50) with chlorzoxazone 6-hydroxylase, compared with DETC-Me sulfoxidase activity in the absence of DDTC (r= 0.09), Polyclonal antibodies against CYP2E1 caused a modest inhibition (30%) of DETC-Me sulfoxidation by human liver microsomes, Anti-CYP3A1 antibodies completely inhibited DETC-Me sulfoxidation by cDNA-expressed CYP3A4. Under similar conditions, DETC-Me sulfoxidation by humanliver microsomes was only partially inhibited by anti-CYP3A1 antibodies. Although studies with the rat and cDNA-expressed cytochrome P450 enzymes suggested that CYP1A2 contributed to DETC-Me sulfoxidation, this reaction was not inhibited by either furafylline (a mechanism-based inhibitor of CYP1A2) or antibodies against CYP1A1/2. A significant role for CYP2C9 was excluded by the inability of sulfaphenazole to inhibit the sulfoxidation of DETC-Me by human liver microsomes, Collectively, these data suggest that multiple cytochrome P450 enzymes can catalyze the sulfoxidation of DETC-Me, In human liver microsomes the CYP2A6, CYP2E1, and CYP3A4/5 all contribute significantly to the sulfoxidationof DETC-Me, it is interesting to note that DDTC, the reduced metabolite of disulfiram, is known to inhibit these same enzymes, The ability of DDTC to black the formation of DETC-Me sulfoxide may explain why the dose of disulfiram required to produce a disulfiram-ethanol reactionin alcoholics is so variable and often inadequate.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/09/20 alle ore 19:39:27