Carcinogenesis Advance Access published online on July 7, 2004
Carcinogenesis, doi:10.1093/carcin/bgh225
© 2004 by Oxford University Press
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1 Department of Pathology, Sasaki Institute, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: midoriy{at}sasaki.or.jp.
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 antiestrogen 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 2-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 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 17
Revised June 18, 2004
Accepted June 22, 2004
CARCINOGENESIS
Dietary indole-3-carbinol promotes endometrial adenocarcinoma development in rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, with induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism
2 The First Department of Pathology, Kanazawa Medical University, Kanazawa, Japan
3 Director, Sasaki Institute, Tokyo Japan
Abstract 
-estradiol (E2) or 5 µg/kg 4-hydroxyestradiol (4HE) subcutaneously twice a week for 12 months. In the uterotrophic assay, neither 500 nor 2000 ppm 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 16
-hydoxylase activity. mRNAs for CYP 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 might play a crucial role in promoting effects of dietary I3C on endometrial adenocarcinoma development.
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