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Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450
Author(s) -
Patel Molini M.,
Bhat Hari K.
Publication year - 2004
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.20005
Subject(s) - carcinogen , estrogen , oxidative stress , carcinogenesis , chemistry , endocrinology , medicine , ethinylestradiol , cytochrome p450 , alpha (finance) , estrogen receptor alpha , estrogen receptor , biology , cancer , metabolism , biochemistry , population , breast cancer , environmental health , research methodology , construct validity , nursing , patient satisfaction
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)‐α‐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 2α (8− iso ‐PGF 2α ), a marker of oxidative stress. Tumor cells were treated with either 17β‐estradiol (E2), a carcinogenic estrogen or 17‐α‐ethinylestradiol (EE), a weakly‐carcinogenic estrogen. Tumor cells were also treated with α‐naphthoflavone, a cytochrome P450 inhibitor, or a combination of α‐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 2α , 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 2α compared with controls. In H301 cells cotreated with α‐naphthoflavone and E2, α‐naphthoflavone inhibited the E2‐induced increase in 8‐ iso ‐PGF 2α . 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. © 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:37–42, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20005