Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450.
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.
Patel
Molini M
MM
Department of Environmental Health Sciences, Columbia University, New York, NY 10032, USA.
Bhat
Hari K
HK
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D006801:Humans; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects
D001571:Benzoflavones; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens; D016877:Oxidants; D004958:Estradiol; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost