2007 Fiscal Year Final Research Report Summary
A new pathway to multiorgan toxicities driven by modulation of steroid-related metabolism through cytothrome P450 induction in the rat liver
| Project/Area Number |
18510065
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Risk sciences of radiation/Chemicals
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| Research Institution | National Institute of Health Sciences (2007)
National Institute of Radiological Sciences (2006) |
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Principal Investigator |
MIDORI Yoshida National Institute of Health Sciences, Division of Pathology, Section Chief (70201861)
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| Project Period (FY) |
2006 – 2007
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| Keywords | enzyme induction / CYP1B1 / Liver / estrogen metabolism / 4-hydorxyestradiol / uterus / rat |
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| Research Abstract |
Recently, we reported that indole-3-carbinol (I3C) and 4-hydroxyestradiol (4HE), a hydroxylation metabolite of 17β-estradiol (E2) promoted rat uterine adenocarcinoma development, and that I3C induced cytochrome P450s (CYPs) in the liver, indicating a hypothesis for a new pathway for multi-target organ toxicity including carcinogenicity potential by modulation of steroid hormone-related metabolism, especially estrogen-metabolism, through CYPs induction in the liver.
Our goal of the present study was to provide evidence to weigh the hypothesis. We mainly focused on 1) What is major CYP enzyme to modulate the metabolism in the liver, 2) Whether in situ modulation of the metabolism plays any roles in the in situ toxicity or carcinogenesis.
We also selected I3C as test compound in the present study. Firstly, we measured 4-hydroxylase as well as 2-hydroxylase, major enzymes leading from E2 to 4HE or 2HE respectively, in the liver of rats treated with long-term 130. As a result, 4-hydroxylase was increased, and expressions of mRNAs for 1A1, 1A2, and 1B1 were increased in the liver. Immunohistochemically, we confirmed the expression. 1B1 has been reported to be a major metabolic enzyme to convert to 4HE from E2, indicating CYP1B1 induction by I3C treatment plays a crucial role in the metabolic modulation 4HE. Secondary, we investigated in situ expression of CYPs in the uterus and 4- and 2-hydroxylase activity in the liver in short-term treatment with I3C in ovariectomized young adult rats. As result, both 4- and 2-hydorxylase increased in I3C treatment in the liver. While short-term treatment with I3C also increased CYP1B1 in the liver, CYP1B1 always expressed in the uterus with or without the treatment. CYP1A1 was induced by I3C. No CYPs were detected immunohistochemically.
These results suggest that estrogen metabolism from E2 to 4HE by CYPs mainly modulate in the liver not in the uterus. CYP IB1 in the liver is a powerful candidate for the modulation.
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