METABOLISM OF CATECHOL ESTROGENS

儿茶酚雌激素的代谢

基本信息

批准号：
2098754
负责人：
TERRENCE J. MONKS
金额：
$ 10.02万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 1996-07-31
项目状态：
已结题

项目摘要

Hormones can play an important role in both the initiation and promotion of cancer. Hormonal carcinogenesis is often characterized by both tissue and species specificity. In many instances, the basis for this specificity is unclear. In addition, the potential role that metabolism plays in hormonal carcinogenesis remains unclear. In this respect, the catechol estrogens have been suggested to be the putative reactive metabolites responsible for some of the carcinogenic effects of estradiol, and the majority of the literature addressing the role of metabolism in hormonal carcinogenicity is derived from studies on these metabolites. Remarkably however, knowledge of the disposition of the catechol estrogens is poorly understood. This proposal therefore addresses these deficiencies and focuses on the in vivo and in vitro metabolism of the catechol estrogens. In particular, we plan to determine the relative importance of catechol estrogen oxidation and thioether formation, and catechol estrogen methylation, to the overall metabolism of catechol estrogens. Several lines of evidence suggest that the quantitative (and perhaps mechanistic) significance of catechol estrogen oxidation and thioether formation may have been underestimated. Indeed, there is a growing body of evidence demonstrating the biological (re)activity of a variety of quinone-thioethers. For example, we have recently shown that the conjugation of certain quinones with glutathione (GSH) leads to the formation of potent and selective nephrotoxicants. Moreover, the National Toxicology Program recently determined that hydroquinone (HQ) was nephrocarcinogenic in rats. We have also described the in vivo formation of several GSH conjugates of HQ, which are nephrotoxic when administered to rats (the role of toxicity [and mitogenesis] in carcinogenicity remains a contentious issue !). In the Golden Syrian hamster, metabolism of estrogens to catechols, and their corresponding ortho-quinones, may be an important step in the nephrocarcinogenic process. The basis of this species specificity is not known. However, while the liver appears proficient at metabolizing estrogens to catecholic metabolites, the kidney exhibits relatively low activity and plasma levels of both estrogens and their catecholic metabolites are low. Although the catechol estrogens are known to interact with thiols, in particular GSH, to form thioether conjugates, the quantitative importance of this pathway remains unclear. We hypothesize that quinone-thioethers derived from the catechol estrogens may play an important mechanistic role in estradiol mediated carcinogenicity. A comprehensive understanding of both the in vivo and in vitro disposition of the catechol estrogens will not only permit a critical evaluation of this hypothesis, but will also provide information essential to assess the role of metabolism in estradiol mediated carcinogenicity and its role in the species specificity.

激素可以在启动和促进中发挥重要作用癌症。激素致癌作用通常以两种组织为特征和物种特异性。在许多情况下，这个基础特异性尚不清楚。另外，代谢的潜在作用荷尔蒙致癌作用的作用尚不清楚。在这方面，已经建议儿茶酚雌激素为推定的反应性代谢物负责某些致癌作用雌二醇和大多数文献解决了激素致癌性中的代谢是从对这些的研究得出的代谢物。但是，很明显地了解处置儿茶酚雌激素知之甚少。因此，该建议解决这些缺陷，并专注于体内和体外儿茶酚雌激素的代谢。特别是，我们计划确定儿茶酚雌激素氧化的相对重要性和硫乙醚的形成和儿茶酚雌激素甲基化至整体儿茶酚雌激素的代谢。几条证据表明儿茶酚的定量（也许是机械）意义雌激素氧化和硫醚形成可能已经低估了。确实，越来越多的证据证明了生物学（重新）各种喹酮thioethers的活性。例如，我们有最近表明，某些喹酮与谷胱甘肽的结合（GSH）导致有效和选择性肾毒性的形成。此外，国家毒理学计划最近确定氢喹酮（HQ）是大鼠的肾癌癌。我们也描述了几个GSH共轭总部的体内形成，给大鼠施用肾毒性（毒性的作用[和促有丝分裂作用]在致癌性中仍然是一个有争议的问题！）。在黄金叙利亚仓鼠，雌激素的代谢，相应的Quinones，可能是肾癌发生过程。该物种特异性的基础不是已知。但是，肝脏似乎精通代谢雌激素对宗教代谢物，肾脏表现出相对较低的雌激素及其儿童的活动和血浆水平代谢物很低。尽管已知儿茶酚雌激素与硫醇，尤其是GSH相互作用，形成硫醇结合物，该途径的定量重要性尚不清楚。我们假设从儿茶酚雌激素得出的喹酮thiotherer 可能在雌二醇介导的重要机械作用致癌性。对体内和儿茶酚雌激素的体外处置不仅允许对该假设的批判性评估，但也将提供信息评估代谢在雌二醇介导的作用至关重要致癌性及其在物种特异性中的作用。