TRANSCRIPTIONAL REGULATION OF CYTOCHROME P450 GENES

细胞色素P450负责代谢活化或 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 在肝脏中表达，它们的基因受不同的 肝细胞富集转录因子。一种新的基因控制模式 发现大鼠CYP 2D 5启动子，其中肝细胞 富集的因子C/EBP-β与增强因子Sp1协同作用。 这些因素对协同性的具体要求是 通过结构功能研究确定。的精确机制 协同性尚未完全理解，但似乎Spl 与C/EBP-β相互作用并刺激其与弱C/EBP结合 CYP 2D 5启动子中的元件。与之密切相关的因子C/EBP α 不能替代C/EBP-β激活CYP 2D 5 转录。为了确定C/EBP-β是否在 在一个完整的动物，C/EBP-β敲除小鼠中调节CYP 2D基因 进行了检查。CYP 2D基因表达在缺乏CYP 2D基因的小鼠中显著降低。 转录因子研究以确定其他 肝细胞富集因子参与P450基因的调控 表达式正在使用条件空鼠标进行， C/EBP-α、HNF-1-α和HNF-4的表达。标准胚胎 这些因子的基因敲除导致胚胎前或胚胎后 杀伤力含有重组信号侧翼外显子的小鼠具有 产生并表现出正常的表型，表明这些 位点不干扰基因表达。Cre重组酶 通过转基因和病毒方法引入， 基因在成年小鼠肝脏中的功能，并确定这些基因的作用。 P450基因表达的影响因素。

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.