Indole-3-carbinol (I3C), found in cruciferous vegetables, has been shown to suppress or promote
carcinogenesis depending on various animal models. Regarding its preventive effects, I3C acts as an anti-
estrogen and can induce apoptosis, but precise mechanisms remain to be determined. Since I3C induces
cytochrome P450 enzymes in the liver, it affects hydroxylation of
estrogens and might therefore be expected to influence endometrial
adenocarcinoma development. The present study was performed to clarify the effects of I3C using a rat two-stage endometrial
carcinogenesis model, focusing on induction of
cytochrome P450s and other
estrogen-metabolic
enzymes in the liver. First, to determine the estrogenic or anti-estrogenic activity, an uterotropic assay was conducted using ovariectomized Donryu rats (experiment 1). Second, to elucidate the 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 p.p.m. I3C in diets for 12 months (experiment 2). In experiment 3, similarly initiated animals received 0 or 2000 p.p.m. I3C in their diet, or 1 microg/kg 17beta-estradiol (E2) or 5 microg/kg
4-hydroxyestradiol (4HE) subcutaneously twice a week for 12 months. In the uterotrophic assay, neither 500 nor 2000 p.p.m. 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 16alpha-hydoxylase activity. mRNAs for
CYP 1A1, 1A2 and 1B1 were increased by I3C treatment, with translation confirmed immunohistochemically. These results suggest that induction of the CYP 1 family in the liver and sequential modulation of
estrogen metabolism to increase 4HE might play a crucial role in promoting the effects of dietary I3C on endometrial
adenocarcinoma development.