Journal Article

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

Alaa F. Badawi, Ercole L. Cavalieri and Eleanor G. Rogan

in Carcinogenesis

Volume 21, issue 8, pages 1593-1599
Published in print August 2000 | ISSN: 0143-3334
Published online August 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.8.1593
Effect of chlorinated hydrocarbons on expression of cytochrome P450 1A1, 1A2 and 1B1 and 2- and 4-hydroxylation of 17β-estradiol in female Sprague–Dawley rats

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Chlorinated hydrocarbons (CHCs) are environmental contaminants that bioaccumulate and hence are detected in human tissues. Epidemiological evidence suggests that the increased incidence of a variety of human cancers, such as lymphoma, leukemia and liver and breast cancers, might be attributed to exposure 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 (CYP)1A1, CYP1A2 and CYP1B1 mRNAs and the consequent 2- and 4-hydroxylation of 17β-estradiol (E2) in female Sprague–Dawley rats. Animals were administered a single dose of the LD50 of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (25 μg/kg), 2,4-dichlorophenoxyacetic acid (2,4-D) (375 mg/kg) and dieldrin (DED) (38 mg/kg) by gavage. Seventy-two hours after treatment, increased expression of CYP1A1, CYP1A2 and CYP1B1 was observed in the liver, kidney and mammary tissue. Since CYP1A and CYP1B1 are the major enzymes catalyzing 2- and 4-hydroxylation of E2, respectively, the effect of these CHCs on the metabolism of E2 was investigated in rat tissues. Formation of 2- and 4-catechol estrogens was increased in a tissue-specific manner in response to treatment. TCDD was the most potent inducer for CYP1 enzyme mRNA and for the 2- and 4-hydroxylation of E2. 2,4-D and DED induced similar responses, but less than that of TCDD. These results suggest that induction of CYP1 family enzymes and consequent increases in estrogen metabolism by CHCs in target tissues may be factors contributing to the biological effects associated with exposure to these agents.

Keywords: AhR, aryl hydrocarbon receptor; BSA, bovine serum albumin; CHCs, chlorinated hydrocarbons; CYP, cytochrome P450; 2,4-D, 2,4-dichlorophenoxyacetic acid; DED, dieldrin; E1, estrone; E2, 17β-estradiol; IS, internal standard; rc, recombinant; TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Journal Article.  6116 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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