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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450.

Authors: Patel, Molini M; Bhat, Hari K

Published In J Biochem Mol Toxicol, (2004)

Abstract: Different estrogens vary in their carcinogenic potential despite having similar hormonal potencies; however, mechanisms of estrogen-induced carcinogenesis remain to be fully elucidated. It has been hypothesized that generation of reactive estrogen-quinones and oxidative stress, both of which result from metabolic activation of estrogens, play an essential role in estrogen-induced carcinogenesis. This hypothesis was tested using the estrogen-receptor (ER)-alpha-positive hamster kidney tumor (H301) and the human breast cancer (MCF-7) cell lines. Estrogens with differing carcinogenic potentials were compared in terms of their capacities to induce 8-iso-prostaglandin F(2alpha) (8- iso-PGF(2alpha)), a marker of oxidative stress. Tumor cells were treated with either 17beta-estradiol (E2), a carcinogenic estrogen or 17-alpha-ethinylestradiol (EE), a weakly-carcinogenic estrogen. Tumor cells were also treated with alpha-naphthoflavone, a cytochrome P450 inhibitor, or a combination of alpha-naphthoflavone and E2 to study the effect of metabolic activation of E2 on E2-induced oxidative stress. H301 cells treated with E2 displayed time- and dose-dependent increases in 8-iso-PGF(2alpha), compared to controls; treatment with 10 nM E2 resulted in a maximal 4-fold induction following 48 h of treatment. In contrast, H301 cells treated with EE did not display an increase in 8-iso-PGF(2alpha) compared with controls. In H301 cells cotreated with alpha-naphthoflavone and E2, alpha-naphthoflavone inhibited the E2-induced increase in 8-iso-PGF(2alpha). These data indicate that a carcinogenic estrogen shows strong oxidant potential, whereas a weakly-carcinogenic estrogen shows poor oxidant potential. Furthermore, inhibiting metabolic activation of a carcinogenic estrogen blocks its oxidant potential. Our data support the hypothesis that metabolic activation and subsequent generation of oxidative stress may play critical roles in estrogen-induced carcinogenesis.

PubMed ID: 14994278 Exiting the NIEHS site

MeSH Terms: Animals; Benzoflavones/pharmacology; Biotransformation/drug effects*; Carcinogens/toxicity*; Cell Line, Tumor; Cricetinae; Cytochrome P-450 Enzyme System/antagonists & inhibitors; Cytochrome P-450 Enzyme System/metabolism*; Dinoprost/analogs & derivatives; Dinoprost/metabolism*; Estradiol/analogs & derivatives; Estradiol/toxicity; Estrogens/toxicity*; Humans; Oxidants/toxicity*; Oxidative Stress/drug effects; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

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