REGULATION OF ETHANOL-INDUCIBLE CYTOCHROME P450 GENE

乙醇诱导细胞色素 P450 基因的调控

• 批准号: 3789488
• 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/3789488
• 关键词: cytochrome P450; dietary lipid; enzyme induction /repression; ethanol; genetic regulation; genetic translation; gestational age; hormone regulation /control mechanism; isoniazid; ketone body; laboratory rat; lymphocyte; nutrition related tag; pharmacogenetics; pregnancy; pyrazines; pyridine

As a continuous ongoing project, the molecular regulatory mechanism of P450IIE was further investigated. We have previously identified and determined the structures of the ethanol-inducible cytochrome P450 (P450IIE1) of both rat and human. We have also demonstrated three distinct types of regulation of P450IIE1 in rat. The three types of upregulation of P450IIE appeared to be present in liver, lung and kidney tissues. The molecular mechanism of P450IIE1 regulation by other exogenous regulators and during pregnancy were further investigated. Pretranlational activation of P450IIE1 during ketosis induced by a fat diet where the elevation of its mRNA level correlated with the levels of acetoacetate and beta-hydroxybutyrate but not with that of acetone which activates P450IIE1 without elevating its mRNA level. Specific translational induction of P450IIE1 by isoniazid and N-heterocyclic compounds such as pyrazine was demonstrated. Pretranslational reduction of P450IIE during pregnancy and rapid reversal upon parturition were studied. The reduction of P450IIE1 during late-term pregnancy indicates a negative hormonal control mechanism which we are currently investigating. In contrast, pentoxyresorufin O-depentylase (associated with P450IIB1/B2) was pretranslationally activated by the same inducer, pyridine. A rapid and sensitive assay for P450IIE1 is being developed for the detection of P450IIE1 expressed in human lymphocytes.

作为一个持续正在进行的项目，分子调节机制 P450IIE进一步研究了。我们以前已经确定了 确定乙醇诱导的细胞色素P450的结构 （P450IIE1）的大鼠和人。 我们还展示了三个 大鼠中P450IIE1的不同类型的调节。 这三种类型的 P450IIE的上调似乎存在于肝脏，肺和肾脏 组织。其他外源性调节P450IIE1的分子机制 监管机构和怀孕期间得到了进一步研究。 脂肪诱导的酮症期间P450IIE1的预后激活 饮食中的mRNA水平与水平相关的饮食 乙酸乙酸酯和β-羟基丁酸酯，但与丙酮的乙酸乙酸酯和乙酸乙酸酯 激活P450IIE1而不升高其mRNA水平。具体的 p450iie1的翻译诱导和n-杂环的。 证明了吡嗪等化合物。 预后还原 怀孕期间的P450IIE和分娩后快速逆转 研究。 晚期怀孕期间P450IIE1的减少表明 我们目前是一种负激素控制机制 调查。 相反，五氧抗瑞替素O-丁基基酶（相关 使用P450IIB1/B2）被同一诱导剂预处理， 吡啶。 正在开发针对P450IIE1的快速而敏感的测定法 在人淋巴细胞中表达的P450IIE1的检测。