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A new pathway to multiorgan toxicities driven by modulation of steroid-related metabolism through cytothrome P450 induction in the rat liver

通过在大鼠肝脏中诱导细胞色素 P450 来调节类固醇相关代谢，从而驱动多器官毒性的新途径

基本信息

批准号：
18510065
负责人：
MIDORI Yoshida
金额：
$ 2.71万
依托单位：
National Institute of Health Sciences (2007)National Institute of Radiological Sciences (2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18510065/
关键词：
enzyme induction CYP1B1 Liver estrogen metabolism 4-hydorxyestradiol uterus rat cytochrome P450 多臓器毒性子宮癌発癌

项目摘要

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.

最近，我们报道了吲哚-3-甲醇（I3C）和4-羟基雌二醇（4HE）（17β-雌二醇（E2）的羟基化代谢物）促进大鼠子宫腺癌的发展，I3C诱导肝脏细胞色素p450 (CYPs)，这表明通过在肝脏中诱导CYPs调节类固醇激素相关代谢，特别是雌激素代谢，可能存在多靶点器官毒性的新途径，包括致癌潜力。我们本研究的目的是提供证据来衡量这一假设。我们主要关注1)哪些主要的CYP酶在肝脏中调节代谢，2)代谢的原位调节是否在原位毒性或致癌作用中起作用。我们也选择了I3C作为本研究的测试化合物。首先，我们测量了长期服用130的大鼠肝脏中4-羟化酶和2-羟化酶，这两种酶分别从E2到4HE和2HE。结果4-羟化酶升高，肝脏中1A1、1A2、1B1 mrna表达升高。免疫组织化学证实了这种表达。据报道，1B1是E2转化为4HE的主要代谢酶，表明I3C处理诱导CYP1B1在代谢调节4HE中起着至关重要的作用。其次，我们研究了短期用I3C治疗卵巢切除的年轻成年大鼠子宫中CYPs的原位表达和肝脏中4-和2-羟化酶的活性。结果，I3C治疗后肝脏中4-和2-羟化酶均升高。短期使用I3C治疗也会增加肝脏中CYP1B1的表达，但无论是否使用I3C治疗，CYP1B1总是在子宫中表达。I3C诱导CYP1A1。免疫组织化学未检测到CYPs。这些结果表明，雌激素从E2到4HE的代谢主要由CYPs在肝脏调节，而不是在子宫。肝脏中的CYP IB1是一个强有力的候选调节。