Induction of cytochrome P450s in the liver and consequent modulation of estrogen metabolism promote uterine carcinogenesis in rats

已知有许多化学物质可以诱导肝脏中的细胞色素P450酶。最近有报道称，某些化学物质会影响雌激素的羟基化，因此可能会影响子宫内膜腺癌的发展。本研究采用大鼠2期子宫内膜癌模型，重点研究细胞色素p450和肝脏中的其他雌激素代谢酶，以阐明细胞色素p450诱导的化学物质的作用。以十字花科蔬菜中发现的吲哚-3-甲醇（I3C）作为细胞色素p450诱导化学物质的候选对照物。根据不同的动物模型，I3C已被证明可以抑制或促进癌变。关于其预防作用，I3C具有抗雌激素作用，可诱导细胞凋亡，但其确切机制尚不清楚。首先，为了确定雌激素或抗雌激素活性，使用切除卵巢的东流大鼠（实验1）进行了子宫变性试验。其次，为了阐明其对子宫内膜致癌性的影响，雌性东柳大鼠在子宫角中注入单剂量的n -乙基-n '-硝基-n -亚硝基胍，喂食0或500 ppm的I3C，持续12个月（实验2）。在实验3中，同样启动的动物在饲料中添加0或2000 ppm的I3C，或每周皮下注射2次1 μg/kg 13β-雌二醇（E2）或5 μg/kg 4-羟基雌二醇（4HE），持续12个月。在子宫营养试验中，500ppm和2000ppm的I3C都没有显示出任何雌激素或抗雌激素活性。在两项子宫致癌性研究中，I3C和4HE增加了子宫腺癌的发病率和/或子宫增殖性病变的多样性，e2治疗有促进的趋势。在肝脏中，I3C治疗持续提高雌二醇2和4羟化酶活性，尤其是后者，但对雌二醇16α-羟化酶活性没有影响。I3C治疗后，1A1,1A2和1B1 mrna增加，免疫组织化学证实了翻译。上述结果提示，诱导肝脏CYP 1家族并依次调节雌激素代谢以增加4HE在膳食I3C对子宫内膜腺癌发展的促进作用中起着至关重要的作用。少

A number of chemicals are known to induce cytochrome P450 enzymes in the liver. Recently certain chemicals have been reported to impact on hydroxylation of estrogens and might therefore be expected to influence endometrial adenocarcinoma development. The present study was performed to clarify effects of cytochrome P450-induced chemicals using a rat 2stage endometrial carcinogenesis model, focusing on cytochrome P450s and other estrogen-metabolic enzymes in the liver. As a positive control chemical, Indole-3-carbinol (I3C), found in cruciferous vegetables, was used a candidate of the cytochrome P450-induced chemicals. I3C 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. First, to determine the estrogenic or anti-estrogenic activity, an uterotropic assay was conducted using ovariectomized Donryu rats (Experiment 1) … More . Secondary, to elucidate 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 13β-estradiol (E2) or 5 μg/kg 4-hydroxyestradiol(4HE) subcutaneously twice a week for 12 months. In the uterotrophic assay, neither 500 ppm nor 2000ppm 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 16α-hydoxylase activity. mRNAs for 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 plays a crucial role in promoting effects of dietary I3C on endometrial adenocarcinoma development. Less