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The role of cytochrome P4503A1/2 in the sex-specific sulfoxidation of the hexachlorobutadiene metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in rats.
Drug Metab Dispos. 1995 Aug; 23(8):861-8.DM

Abstract

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)

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Publisher Full Text

Authors+Show Affiliations

Werner M
Institut für Toxikologie, Universität Würzburg, Germany.
Birner G
No affiliation info available
Dekant W
No affiliation info available

MeSH

AcetylcysteineAnimalsBiotransformationButadienesCarcinogensChromatography, High Pressure LiquidCytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemEnzyme InductionFemaleIn Vitro TechniquesMaleMicrosomes, LiverMixed Function OxygenasesRatsRats, WistarSex CharacteristicsSteroid HydroxylasesSulfoxides

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

7493554

Citation

Werner, M, et al. "The Role of Cytochrome P4503A1/2 in the Sex-specific Sulfoxidation of the Hexachlorobutadiene Metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in Rats." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 23, no. 8, 1995, pp. 861-8.
Werner M, Birner G, Dekant W. The role of cytochrome P4503A1/2 in the sex-specific sulfoxidation of the hexachlorobutadiene metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in rats. Drug Metab Dispos. 1995;23(8):861-8.
Werner, M., Birner, G., & Dekant, W. (1995). The role of cytochrome P4503A1/2 in the sex-specific sulfoxidation of the hexachlorobutadiene metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in rats. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 23(8), 861-8.
Werner M, Birner G, Dekant W. The Role of Cytochrome P4503A1/2 in the Sex-specific Sulfoxidation of the Hexachlorobutadiene Metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in Rats. Drug Metab Dispos. 1995;23(8):861-8. PubMed PMID: 7493554.
* Article titles in AMA citation format should be in sentence-case
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. AU - Werner,M, AU - Birner,G, AU - Dekant,W, PY - 1995/8/1/pubmed PY - 1995/8/1/medline PY - 1995/8/1/entrez SP - 861 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 23 IS - 8 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) SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/7493554/The_role_of_cytochrome_P4503A1/2_in_the_sex_specific_sulfoxidation_of_the_hexachlorobutadiene_metabolite_N_acetyl_S__pentachlorobutadienyl__L_cysteine_in_rats_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7493554 DB - PRIME DP - Unbound Medicine ER -