Renal tumorigenicity of 1,1-dichloroethene in mice: the role of male-specific expression of cytochrome P450 2E1 in the renal bioactivation of 1,1-dichloroethene.
1,1-Dichloroethene is used as intermediate in the manufacture of polymers. In male mice, 1,1-dichloroethene caused renal tumors after inhalation. Renal tumors were not observed in female mice or in both sexes of rats. We investigated the metabolic basis for the species- and sex-specific nephrotoxicity and tumorigenicity of 1,1-dichloroethene. Kidney microsomes from male mice biotransformed 1,1-dichloroethene to chloroacetic acid; the amounts of chloroacetic acid formed were dependent on the hormonal status of the animals and correlated well with the ability of kidney microsomes to oxidize p-nitrophenol and chlorozoxazone, specific substrates for cytochrome P450 2E1. In kidney microsomes from naive females, significantly lower rates of oxidation of 1,1-dichloroethene, p-nitrophenol, and chlorozoxazone were observed; oxidation could be induced by testosterone. With a rabbit anti-rat liver cytochrome P450 2E1 antibody, a cross-reactive protein was detected in male mouse kidney microsomes with a molecular weight very similar to that of rat liver cytochrome P450 2E1; the expression of this protein was regulated by testosterone and correlated well with the ability of the microsomes to oxidize p-nitrophenol, chlorozoxazone, and 1,1-dichloroethene. When the relative cytochrome P450 2E1 contents of renal microsomes of male mice from different strains were compared, differences in the expression of cytochrome P450 2E1 were observed. Moreover, nephrotoxicity in Swiss-Webster mice after inhalation of 1,1-dichloroethene was observed only in males and testosterone-treated females, but not in naive females. In kidney microsomes obtained from both sexes of rats and in six samples of human kidney (male donors), no p-nitrophenol oxidase activity was detected. These data suggest that cytochrome P450 2E1 or a P450 enzyme with very similar molecular weight, substrate specificities, and immunological properties is expressed only in male mouse kidney and bioactivates 1,1-dichloroethene.
Speerschneider
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P
Institut für Toxikologie, Universität Würzburg, FRG.
Dekant
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D000085:Acetates / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D001711:Biotransformation; D015153:Blotting, Western; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002753:Chlorzoxazone / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004000:Dichloroethylenes / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D051381:Rats; D012737:Sex Factors; D013045:Species Specificity; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology
D000085:Acetates; D002273:Carcinogens; D004000:Dichloroethylenes; D009596:Nitrophenols; C029297:vinylidene chloride; D013739:Testosterone; C006972:chloroacetic acid; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D002753:Chlorzoxazone; C024836:4-nitrophenol