{'fraction_non_alphanumeric': 0.03974706413730804, 'fraction_numerical': 0.032068654019873535, 'mean_word_length': 6.0993589743589745, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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)‐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 F2α (8− iso‐PGF2α), 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‐PGF2α, 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‐PGF2α compared with controls. In H301 cells cotreated with α‐naphthoflavone and E2, α‐naphthoflavone inhibited the E2‐induced increase in 8‐iso‐PGF2α. 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