Effect of chlorinated hydrocarbons on expression of cytochrome P450 1A1, 1A2 and 1B1 and 2-and 4-hydroxylation of 17 beta-estradiol in female Sprague-Dawley rats

Chlorinated hydrocarbons (CHCs) are environmental contaminants that bioaccu mulate and hence are detected in human tissues. Epidemiological evidence su ggests that the increased incidence of a variety of human cancers, such as lymphoma, leukemia and liver and breast cancers, might be attributed to exp osure to these agents. The ability of CHCs to disrupt estrogen homeostasis is hypothesized to be responsible for their biological effects, The present study examined the effect of CHCs on the expression of cytochrome P450 (CY P)1A1, CYP1A2 and CYP1B1 mRNAs and the consequent 2- and 4-bydroxylation of 17 beta-estradiol (E-2) in female Sprague-Dawley rats. Animals were admini stered a single dose of the LD50 of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TC DD) (25 mu g/kg), 2,4-dichlorophenoxyacetic acid (2,4-D) (375 mg/kg) and di eldrin (DED) (38 mg/kg) by gavage. Seventy-two hours after treatment, incre ased expression of CYP1A1, CYP1A2 and CYP1B1 was observed in the liver, kid ney and mammary tissue. Since CYP1A and CYP1B1 are the major enzymes cataly zing 2- and 4-hydroxylation of E-2, respectively, the effect of these CHCs on the metabolism of E-2 was investigated in rat tissues. Formation of 2- a nd 4-catechol estrogens was increased in a tissue-specific manner in respon se to treatment. TCDD was the most potent inducer for CYP1 enzyme mRNA and for the 2- and 4-hydroxylation of E-2, 2,4-D and DED induced similar respon ses, but less than that of TCDD, These results suggest that induction of CY P1 family enzymes and consequent increases in estrogen metabolism by CHCs i n target tissues may be factors contributing to the biological effects asso ciated with exposure to these agents.