Induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism promote uterine carcinogenesis in rats

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A number of chemicals are known to induce cytochrome P450 enzymes in the liver. Recently certain chemicals have been reported to impact on hydroxylation of estrogens and might therefore be expected to influence endometrial adenocarcinoma development. The present study was performed to clarify effects of cytochrome P450-induced chemicals using a rat 2stage endometrial carcinogenesis model, focusing on cytochrome P450s and other estrogen-metabolic enzymes in the liver. As a positive control chemical, Indole-3-carbinol (I3C), found in cruciferous vegetables, was used a candidate of the cytochrome P450-induced chemicals. I3C has been shown to suppress or promote carcinogenesis depending on various animal models. Regarding its preventive effects, I3C acts as an antiestrogen and can induce apoptosis, but precise mechanisms remain to be determined. First, to determine the estrogenic or anti-estrogenic activity, an uterotropic assay was conducted using ovariectomized Donryu rats (Experiment 1) … More . Secondary, to elucidate effects on endometrial carcinogenicity, female Donryu rats initiated with a single dose of N-ethyl-N'-nitro-N-nitrosoguanidine into a uterine horn were fed 0 or 500 ppm I3C in diets for 12 months (Experiment 2). In Experiment 3,similarly initiated animals received 0 or 2000 ppm I3C in diet, or 1 μg/kg 13β-estradiol (E2) or 5 μg/kg 4-hydroxyestradiol(4HE) subcutaneously twice a week for 12 months. In the uterotrophic assay, neither 500 ppm nor 2000ppm of I3C showed any estrogenic or anti-estrogenic activity. In the two uterine carcinogenicity studies, I3C and 4HE increased incidences of uterine adenocarcinomas and/or multiplicities of uterine proliferative lesions, E2-treatment being associated with a tendency for promotion. In the liver, I3C treatment consistently elevated estradiol 2 and 4 hydroxylase activities, in particular the latter, but without effects on estradiol 16α-hydoxylase activity. mRNAs for 1A1,1A2 and 1B1 were increased by I3C treatment, with translation confirmed immunohistochemically. These results suggest that induction of CYP 1 family in the liver and sequential modulation of estrogen metabolism to increase 4HE plays a crucial role in promoting effects of dietary I3C on endometrial adenocarcinoma development. Less