ALDO-KETO REDUCTASES AS PART OF CHEMICAL STRESS RESPONSE

描述：醛酮还原酶提供对环境和生物的保护， 通过活性醛解毒的营养毒素和致癌物 能够改变细胞大分子。化学应激诱导 一系列解毒酶的表达。因此，黄曲霉毒素还原酶 由乙氧喹和其他抗氧化剂引起。最近的研究表明， 乙氧喹和抗生素衣霉素也诱导醛还原酶，另一个 醛酮还原酶家族的成员。人类的一个关键因素 醛还原酶基因启动子与转录因子CHOP结合， 在暴露于化学应激的细胞中诱导。初步结果表明 CHOP介导醛还原酶表达的诱导， 黄曲霉毒素和醛还原酶是细胞化学应激的一部分 反应系统，因此它们的表达被诱导以响应毒性损伤。 本申请提出：a）评估生理学上的能力， 诱导醛还原酶表达的相关化合物， 两种还原酶的诱导是否通过CHOP依赖性途径。 B）测试两大类化合物：毒性底物和 已知诱导黄曲霉毒素还原酶和其它药物的化学保护剂 代谢酶（如谷胱甘肽-S-转移酶）。C）测试选定的 刺激其诱导CHOP的能力。D）确定CHOP是否发挥作用 通过测试CHOP的作用来诱导黄曲霉毒素和醛还原酶 过度表达和缺陷，以及已知的CHOP诱导剂对 还原酶表达。e）克隆并测序黄曲霉毒素还原酶启动子， 检查它的CHOP结合元件和响应元件，以指导 其他解毒基因的抗氧化诱导。了解自然 醛和黄曲霉毒素还原酶表达的调控机制将 可能有助于预防有害和致癌的影响， 有毒的醛类，并提供了一个基础，以确定人口与 对某些环境因素的敏感性增加。

DESCRIPTION: Aldo-keto reductases provide protection against environmental and nutritional toxins and carcinogens by detoxification of reactive aldehydes capable of modifying cellular macromolecules. Chemical stress induces the expression of a number of detoxification enzymes. Thus, aflatoxin reductase is induced by ethoxyquin and other antioxidants. Recently it was shown that ethoxyquin and antiobiotic tunicamycin also induce aldehyde reductase, another member of the aldo-keto reductase family. A crucial element of the human aldehyde reductase gene promoter binds transcription factor CHOP, which is induced in cells exposed to chemical stress. Preliminary results suggest that CHOP mediates the induction of aldehyde reductase expression and that both aflatoxin and aldehyde reductases are part of the cellular chemical stress response system, hence their expression is induced in response to toxic insult. The application proposes to: a) evaluate the ability of physiologically relevant compounds to induce aldehyde reductase expression and to find out whether induction of both reductases goes through the CHOP-dependent pathway. B) test the compounds of the two major groups: toxic substrates and chemoprotectors that are known to induce aflatoxin reductase and other drug metabolizing enzymes (e.g. glutathione-S-transferase). C) test the Selected stimuli for their ability to induce CHOP. D) determine whether CHOP plays a role in inducing aflatoxin and aldehyde reductase by testing the effect of CHOP overexpression and deficiency, and known CHOP-inducing agents on the of the reductases expression. e) clone and sequence aflatoxin reductase promoter and examine it for a CHOP-binding element and response elements described to direct antioxidant induction in other detoxification genes. Understanding the nature and mechanism of regulation of aldehyde and aflatoxin reductase expression will potentially assist in the prevention of harmful and carcinogenic effects of toxic aldehydes as well as provide a basis for identifying populations with increased susceptibility to certain environmental agents.