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.