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. Yoshida M, Katashima S, Ando J, Tanaka T, Uematsu F, Nakae D, Maekawa A. Department of Pathology, Sasaki Institute, Tokyo, Japan and The First Department of Pathology, Kanazawa Medical University, Kanazawa, Japan. Carcinogenesis. 2004 Nov;25(11):2257-64. Epub 2004 Jul 07 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 mug/kg 17beta-estradiol (E2) or 5 mug/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.
Development of a multi-organ rat model for evaluating chemopreventive agents: efficacy of indole-3-carbinol. Stoner G, Casto B, Ralston S, Roebuck B, Pereira C, Bailey G. Division of Environmental Health Sciences, School of Public Health, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA. stoner.21@osu.edu Carcinogenesis. 2002 Feb;23(2):265-72. Indole-3-carbinol (I-3-C) is among the most widely and popularly
known antiestrogens. Due to its putative chemopreventive action, I-3-C
is being marketed to the general public in health food establishments.
Although it has been demonstrated to prevent cancer in animal bioassays,
I-3-C also acts as a promoter in the liver and colon. Because of this
potential dual biological activity, it is important to investigate both
the inhibitory and promotional activities of I-3-C in multi-organ tumorigenesis
animal models. 7,12-Dimethylbenz[a]anthracene, aflatoxin B1 and azoxymethane
were used to initiate mammary, liver and colon carcinogenesis, respectively
in female Sprague-Dawley rats. The rats were fed continuously on a diet
containing I-3-C for 25 weeks after initiation. I-3-C treatment was begun
one week after the last carcinogen treatment had been administered. I-3-C
treatment resulted in a delay in latency of mammary tumor formation, but
did not alter tumor incidence or multiplicity among survivors. In the
colon, the protocol produced a 40% decrease in aberrant colon crypt foci.
However, in the liver, it strongly-induced GST-P foci in carcinogen-treated
(a four-fold increase in volume percent foci) and in the vehicle controls
(a 69-fold increase). These data support previous findings in other rodent
and fish tumor models that I-3-C both inhibits and promotes carcinogenesis.
The results of this study clearly demonstrate that I-3-C is not an appropriate
chemoprotective agent for human use, in spite of its effects in the breast
and colon in this rat animal model.
Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Dashwood RH. Department of Environmental Biochemistry, University of Hawaii, Honolulu 96822, USA. dashwood@hawaii.edu Chem Biol Interact. 1998 Mar 12;110(1-2):1-5. Indole-3-carbinol (I3C) is one of several compounds in brassica vegetables that demonstrate anticarcinogenic effects in experimental animals. A review of Medline and CancerLit databases indicated that interest in I3C, as a cancer chemopreventive agent, has increased significantly in the past 5-10 years. Whereas most studies report inhibitory or protective effects of I3C in vivo, a few provide clear evidence for promotion or enhancement of carcinogenesis, depending upon the initiator, exposure protocol and species. In the absence of detailed information on the inhibitory and in particular, promotional mechanisms, it would seem advisable to proceed with caution before including I3C in extensive human clinical trials.
Multiple dietary factors in the enhancement of dimethylhydrazine carcinogenesis: main effect of indole-3-carbinol. Pence BC, Buddingh F, Yang SP. J Natl Cancer Inst. 1986 Jul;77(1):269-76 The effects of multiple dietary influences on 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8]-induced colon cancer in rats were studied. A 2(4) factorial experimental design was used to examine the main and interactive effects of 15% wheat bran (WB), 1% cholesterol (CH) with cholic acid, 20% beef tallow (BT), and 0.1% indole-3-carbinol (IC) on 160 male F344 rats treated ip with DMH (10 mg/kg) weekly for 16 weeks. The test diets were fed for 3 weeks before, 16 weeks during, and 12 weeks after DMH administration. At necropsy, total weight gain, liver and spleen weights, serum CH levels, liver aryl hydrocarbon hydroxylase (AHH) activity, and the size, number, incidence, and location of intestinal tumors were analyzed for dietary factor effects. The most significant inducer of tumors was the combination of CH + BT + IC acting in synergism. The single main effect most responsible for tumor morbidity was IC, which appeared to enhance tumorigenesis via its role as an inducer of AHH activity. The WB decreased tumor incidence and burden when added to diets also containing CH, but it otherwise increased tumor burden per tumor-bearing animal and incidence in all other diets. This study demonstrated the need for examining synergistic and antagonistic interactions among dietary initiators and/or promoters of colon carcinogenesis, as well as implicating IC as a significant factor in the development of DMH-induced tumors in rats
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