TY - JOUR T1 - The role of cytochrome P4503A1/2 in the sex-specific sulfoxidation of the hexachlorobutadiene metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in rats. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 861 LP - 868 VL - 23 IS - 8 AU - M Werner AU - G Birner AU - W Dekant Y1 - 1995/08/01 UR - http://dmd.aspetjournals.org/content/23/8/861.abstract N2 - Hexachlorobuta-1,3-diene (HCBD) is a selective nephrotoxin and a potent nephrocarcinogen in rodents. Its toxicity and carcinogenicity is based on a multistep bioactivation pathway. Glutathione conjugation seems to be the only bioactivation pathway for HCBD leading to reactive intermediates, which are thought to be responsible for the observed nephrotoxic effects. Recent in vivo studies revealed a novel urinary metabolite in male, but not female, rats after administration of [14C]HCBD. This metabolite was identified as (E)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine-sulfoxide (N-Ac-PCBC-SO). The objective of this study was to elucidate the enzyme(s) involved in this particular oxidation and to find an explanation for the sex differences in the formation of N-Ac-PCBC-SO. Both cytochrome P450 and flavin-containing monooxygenases (FMO) may catalyze the oxidation of N-Ac-PCBC-SO. The use of various competitive and allosteric inhibitors of cytochrome P450 and FMO (i.e. metyrapone, N-benzylimidazole, thiobenzamide, CO, n-octylamine, and heat inactivation studies) showed that the sulfoxidation of (E)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)- L-cysteine is catalyzed by cytochrome P450 enzymes. In microsomes from male rats pretreated with pyridine, phenobarbital, and dexamethasone, an increase in the rates of sulfoxide formation was only seen in microsomes from dexamethasone- and phenobarbital-induced animals. Moreover, troleandomycin, a selective chemical inhibitor for enzymes of the cytochrome P4503A family, inhibited sulfoxide formation by > 80%. Correlation of sulfoxide formation with testosterone 6 beta-hydroxylation, a marker of cytochrome P4503A1/2 in the rat, underlined the finding that cytochrome P4503A is the predominant cytochrome P450 responsible for this particular oxidation.(ABSTRACT TRUNCATED AT 250 WORDS) ER -