REGULATION OF ETHANOL-INDUCIBLE CYTOCHROME P450 GENE

乙醇诱导细胞色素 P450 基因的调控

• 批准号: 3745201
• 负责人: B J SONG
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3745201
• 关键词: alcoholic liver cirrhosis; animal tissue; brain cell; cytochrome P450; ethanol; gel mobility shift assay; gene expression; gene induction /repression; genetic promoter element; genetic regulation; genetic translation; isozymes; liver cells; nuclear runoff assay; posttranslational modifications; pregnancy; protein sequence

We previously cloned and demonstrated four distinct types of regulation of P450llE1. During the past year, we demonstrated two additional mechanisms of P450llE1 regulation: translational activation of P45OllE1 by isoniazid and pyrazine; and pretranslational suppression of hepatic P45OllE1 during pregnancy. Specific translational induction of P45OllE1 by isoniazid and pyrazine was demonstrated. However, pyridazine and pyrimidine, two stereoisomers of pyrazine, did not activate P45OllE1, indicating a more inflexible structural requirement for P450llE1 mRNA translation into its protein. In contrast, pyrrole with five-membered ring structure reduced P45OllE1 activity resulting from rapid reversal (within 1 day) upon parturition were also demonstrated. Exogenously administered steroids (progesterone, estrogen, and thyroxine) and peptide growth factors (placental lactogen, prolactin, and growth hormone) did not cause significant changes in P45OllE1 level. The changes in P45OllE1 was only observed in liver but not in extrahepatic tissues, suggesting a potential role of hepatocyte growth factor in P45OllE1 regulation. In collaboration with Dr. Ravindranath, the presence of P45OllE1 in brain and its induction after chronic ethanol drinking were demonstrated. We also showed that P45OllE1 can be phosphorylated by protein kinase C, cAMP dependent protein kinase or calmodulin-dependent protein kinase.

我们以前克隆并展示了四种不同类型的调节 P450LLE1。在过去的一年中，我们展示了另外两个机制 P450LLE1调节：Isoniazid的P45olle1的翻译激活 和吡嗪；并预抑制肝p45olle1 怀孕。 Isoniazid和 吡嗪被证明。但是，吡啶嗪和嘧啶，两个 吡嗪的立体异构体未激活p45olle1，表明更多 P450LLE1 mRNA转化为其的僵化结构要求 蛋白质。相比之下，具有五元环结构降低的吡咯 p45olle1活性是由快速逆转（1天之内）产生的 还证明了分娩。外源给予类固醇 （孕酮，雌激素和甲状腺素）和肽生长因子 （胎盘泌乳，催乳素和生长激素）没有引起 p45olle1水平的重大变化。 P45olle1的变化仅是 在肝脏中观察到，但在肝外组织中未观察到 肝细胞生长因子在P45OLLE1调节中的作用。合作 与Ravindranath博士一起，大脑中P45olle1的存在及其诱导 慢性乙醇饮用后。我们还表明 p45olle1可以被蛋白激酶C磷酸化，cAMP依赖蛋白 激酶或钙调蛋白依赖性蛋白激酶。