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NADPH P450 REDUCTASE--THYROID HORMONE REGULATION

NADPH P450 还原酶--甲状腺激素调节

基本信息

批准号：
6523702
负责人：
DAVID J WAXMAN
金额：
$ 21.32万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2004-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6523702
关键词：
NAD(P)H oxidoreductase catechols cytochrome P450 enzyme induction /repression enzyme mechanism hormone regulation /control mechanism laboratory rat liver metabolism microsomes oxidation reduction reaction oxidative stress posttranscriptional RNA processing quinones thyroid hormones toxin metabolism unspecific monooxygenase

项目摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) NADPH-cytochrome P450 reductase (P450 reductase) is a microsomal flavoprotein that transfers electrons from NADPH to microsomal cytochrome P450. It is expressed in liver and many extrahepatic tissues and is an obligatory, often rate-limiting component of microsomal P450-linked carcinogen activation and drug and alcohol metabolism reactions. While the influence of endogenous regulators on individual P450 enzymes and their genes have been studied extensively, much less is understood about the regulation of P450 reductase by endogenous hormonal factors. Studies carried out using the rat model have established that normal, physiological levels of thyroid hormone are required for full expression of hepatic P450 reductase mRNA, protein and enzyme activity, as well as P450 reductase-dependent xenobiotic metabolism. Moreover, while enhanced gene transcription was found to contribute to the thyroid hormone-dependent expression of P450 reductase mRNA, post-transcriptional mechanisms are key to the regulation of P450 reductase protein and activity. The studies described in this new grant application are designed to elucidate the post-transcriptional regulatory mechanisms by which thyroid hormone modulates P450 reductase expression under conditions of hyperthyroidism and hyperthyroidism, and to evaluate the implications of this modulation for P450 reductase-catalyzed quinone and carcinogen activation via redox cycling. The major goals of this proposal are (a) to elucidate the post-transcriptional mechanisms through which thyroid hormone regulates liver P450 reductase mRNA expression, (b) to characterize the role of thyroid hormone in the translational and post-translational control of P450 reductase protein and activity, and (c) to evaluate the effects of thyroid hormone-dependent alterations in cellular P450 reductase activity on the metabolism and redox cycling of quinones, catechols and related carcinogens, and to elucidate the impact on the cell's adaptive response to oxidative stress. The detailed understanding of the multiple actions of thyroid hormone on P450 reductase expression and foreign chemical metabolism provided by these studies will help elucidate some of the underlying mechanisms through which hormonal environment can influence xenobiotic-induced redox cycling, and may ultimately help to identify individuals who are more susceptible to oxidative stress as a consequence of alterations in thyroid hormone status.

描述：（改编自研究者摘要）NADPH-细胞色素P450 还原酶（P450还原酶）是一种微粒体黄素蛋白，电子从NADPH到微粒体细胞色素P450。在肝脏中表达和许多肝外组织，是一个强制性的，往往是限速的微粒体P450相关致癌物激活成分与药物和酒精代谢反应。而内源性调节因子对个别P450酶及其基因已被广泛研究，关于内源性P450还原酶的调节，荷尔蒙因素使用大鼠模型进行的研究已经确定，正常的，生理水平的甲状腺激素是需要充分肝脏P450还原酶mRNA、蛋白表达及酶活性作为P450还原酶依赖的异生物质代谢。此外，虽然增强基因转录被发现有助于甲状腺激素依赖性 P450还原酶mRNA的表达，转录后机制是关键， P450还原酶蛋白及其活性的调节。中描述的研究这项新的拨款申请旨在阐明转录后甲状腺激素调节P450还原酶的调节机制在甲状腺功能亢进和甲状腺功能亢进的条件下表达，评估这种调节对P450还原酶催化的醌和致癌物通过氧化还原循环活化。本项目的主要目标是建议是（a）阐明转录后机制，甲状腺激素调节肝P450还原酶mRNA表达，（B）描述甲状腺激素在翻译和 P450还原酶蛋白和活性的翻译后控制，和（c）评估甲状腺激素依赖性改变对细胞P450的影响还原酶活性对醌类、儿茶酚类代谢和氧化还原循环的影响和相关致癌物质，并阐明对细胞适应性的影响，氧化应激反应。详细了解多重甲状腺激素对P450还原酶表达和外源化学物质的作用这些研究提供的代谢将有助于阐明一些潜在的激素环境可以影响外源性诱导的机制氧化还原循环，并可能最终有助于确定谁是更多的个人易受氧化应激的影响，这是甲状腺功能改变的结果。激素状态