TRANSCRIPTIONAL REGULATION OF CYTOCHROME P450 GENES

细胞色素P450负责代谢激活或 化学致癌物的灭活。他们也是校长 代谢治疗用药物的酶。大多数P450都是 在肝脏中表达，它们的基因受到不同的控制 肝细胞富集型转录因子。一种新的基因控制模式 发现了大鼠细胞色素P450 2 D5启动子，其中肝细胞 浓缩因子C/EBP-β与Enbiqurtoris因子SPL协同作用。 这些因素对协作性的具体要求是 经结构功能研究鉴定。它的精确机制是 协作性还没有完全被理解，但似乎SPL 与C/EBP-β相互作用并刺激其与弱C/EBP结合 基因启动子中的一个元件。密切相关的C/EBP-α因子 不能替代C/EBP-β激活CYP2D5 抄写。为了确定C/EBP-beta在 在完整动物--C/EBP-β缺失小鼠中调节细胞色素P450 2 D基因 被检查过了。在缺乏的小鼠中，CYP2D基因的表达显著降低 转录因子。研究以确定是否有其他 富肝细胞因子参与P450基因的调控 正在使用条件空小鼠进行表达，这些小鼠缺乏 C/EBP-α、人神经营养因子-L-α、人神经营养因子-4的表达。标准胚胎 这些因子的基因敲除会导致胚胎前或胚胎后 杀伤力。在外显子两侧含有重组信号的小鼠 并表现出正常的表型表明这些 这些位点不会干扰基因表达。Cre重组酶是 通过转基因和病毒方法引入，以破坏 成年小鼠肝脏中的基因功能及其作用 影响P450基因表达的因素。

Cytochromes P450 are responsible for the metabolic activation or inactivation of chemical carcinogens. They are also the principal enzymes that metabolize therapeutically-used drugs. Most P450s are expressed in the liver and their genes are under control of different hepatocyte enriched transcription factors. A novel mode of gene control was uncovered with the rat CYP2D5 promoter in which the hepatocyte enriched factor C/EBP-beta cooperates with the enbiqurtoris factor Spl. Specific requirements of these factors for cooperativity were identified by structure function studies. The precise mechanism of cooperativity is not completely understood but it appears that Spl interacts with C/EBP-beta and stimulates its binding to a weak C/EBP element in the CYP2D5 promoter. The closely related factor C/EBP-alpha is not able to substitute for C/EBP-beta in activation CYP2D5 transcription. In order to determine whether C/EBP-beta is active in regulating CYP2D genes in an intact animal, the C/EBP-beta null mouse was examined. CYP2D gene expression was markedly lower in mice lacking the transcription factor. Studies to determine whether other hepatocyte-enriched factors are involved in regulating P450 gene expressions are in progress using conditional null mice that lack expression of C/EBP-alpha, HNF-l-alpha, and HNF-4. Standard embryonic gene knockouts of these factors result in either pre or post-embryonic lethality. Mice containing the recombination signal flanking exons have been produced and exhibit a normal phenotypes indicating that these sites do not interfere with gene expression. The Cre recombinase is being introduced by transgenic and viral methods in order to destroy gene function in livers of adult mice and determine the roles of these factors in P450 gene expression.