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

已知许多化学物质可诱导肝脏中的细胞色素P450酶。最近有报道某些化学物质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。本研究采用大鼠子宫内膜癌2阶段模型，观察细胞色素P450和其他雌激素代谢酶对子宫内膜癌发生的影响。作为阳性对照化学品，使用在十字花科蔬菜中发现的吲哚-3-甲醇（I3 C）作为细胞色素P450诱导化学品的候选物。I3 C已被证明抑制或促进致癌作用，这取决于各种动物模型。关于其预防作用，I3 C作为一种抗雌激素，可以诱导细胞凋亡，但确切的机制仍有待确定。首先，为了确定雌激素或抗雌激素活性，使用切除卵巢的Donryu大鼠进行子宫促生长试验（实验1）。 ...更多信息 .其次，为了阐明对子宫内膜致癌性的影响，在雌性Donryu大鼠的子宫角中给予单剂量的N-乙基-N '-硝基-N-亚硝基胍，连续12个月喂食0或500 ppm I3 C的饲料（实验2）。在实验3中，类似启动的动物在饲料中接受0或2000 ppm I3 C，或每周两次皮下注射1 μg/kg 13β-雌二醇（E2）或5 μg/kg 4-羟基雌二醇（4 HE），持续12个月。在子宫营养试验中，500 ppm和2000 ppm的I3 C均未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，I3 C和4 HE增加了子宫腺癌的发生率和/或子宫增生性病变的多样性，E2治疗与促进趋势相关。在肝脏中，I3 C处理持续升高雌二醇2和4羟化酶活性，尤其是后者，但对雌二醇16α-羟化酶活性无影响。I3 C处理增加了1A 1、1A 2和1B 1的mRNA，并通过免疫化学证实了翻译。这些结果表明，在肝脏中诱导的EST 1家族和顺序调节雌激素代谢，以增加4 HE在饮食I3 C促进子宫内膜腺癌的发展的影响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