NADPH P450 REDUCTASE--THYROID HORMONE REGULATION

描述：(改编自《调查者摘要》)NADPH-细胞色素P450 还原酶(P450还原酶)是一种微体黄素蛋白 从NADPH到微粒体细胞色素P450的电子。它在肝脏中表达 和许多肝外组织，是一种强制性的，通常是限速的 微粒体P450相关致癌物激活成分与药物和酒精 新陈代谢反应。而内源性调节因子对细胞周期的影响 单个P450酶及其基因已经被广泛研究了很多 关于内源对P450还原酶的调节作用了解较少 荷尔蒙因素。使用老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完全需要的 肝脏P450还原酶基因、蛋白和酶活性的表达 作为P450还原酶依赖的异体代谢。此外，虽然增强了 基因转录被发现与甲状腺激素依赖有关 P450还原酶mRNA的表达，转录后机制是关键 P450还原酶蛋白和活性的调节。中描述的研究 这项新的拨款申请旨在阐明转录后的 甲状腺激素调节P450还原酶的调控机制 在甲亢和甲亢条件下的表达，以及 评估这种调节对P450还原酶催化的影响 通过氧化还原循环激活对苯二酚和致癌物。这次会议的主要目标是 建议是(A)阐明转录后机制，通过这些机制 甲状腺激素调节肝脏P450还原酶mRNA表达，(B)至 描述甲状腺激素在翻译和翻译过程中的作用 P450还原酶蛋白和活性的翻译后调控，以及(C)到 评价甲状腺激素依赖性改变对细胞P450的影响 对苯二酚、儿茶酚代谢和氧化还原循环的还原酶活性 和相关致癌物，并阐明对细胞适应性的影响 对氧化应激的反应。详细了解了多个 甲状腺激素对P450还原酶表达及外源化学物质的影响 这些研究提供的新陈代谢将有助于阐明一些潜在的 激素环境影响异种生物诱导的机制 氧化还原自行车，并最终可能有助于识别谁更 由于甲状腺的改变而易受氧化应激的影响 荷尔蒙状况。

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.