TRANSCRIPTIONAL REGULATION OF CYTOCHROME P450 GENES

细胞色素P450具有复杂多样的调控回路。 某些P450形式以非常低的水平表达，并且由 外来化合物如多环芳烃， 苯巴比妥和氯贝丁酯。 其他P450是组成型表达的。 这些酶在肝组织中富集，并且它们的表达是 在发展过程中被激活。 这只老鼠被用来做实验 模型来研究组织特异性，发育- CYP 2家族中P450的程序化转录。 各种 使用的实验方法包括体外转录， 异源启动子转录测定，反式激活转录 测定和体外DNA结合测定，包括，凝胶迁移率变化， DNA酶I足迹和甲基化干扰，以确定 CYP 2C 6、CYP 2 E1和CYP 2D 5基因的调节机制。 这些 研究表明，CYP 2C 6启动子受肝脏控制， 富含转录因子DBP，但能够结合C/EBP- α、C/EBP-β和DBP。 尽管C/EBP蛋白能够 结合调控区，它们不能激活CYP 2C 6 启动子 CYP 2 E1受因子HNF-1-α和CYP 2D 5控制 部分由Sp1和C/EBP-β调节。 CYP 7A 1，胆固醇7- α-羟化酶受DBP、C/EBP-α和C/EBP-β调节。 这些数据表明，发育激活的P450表达 大鼠肝脏中的基因部分是由于 肝脏富集的转录因子。

Cytochromes P450 have complex and diverse regulatory control circuits. Certain P450 forms are expressed at very low levels and are induced by foreign compounds such as polycyclic aromatic hydrocarbons, phenobarbital, and clofibrate. Other P450s are constitutively expressed. These enzymes are enriched in liver tissues and their expression is activated during development. The rat has been used as an experimental model to investigate the mechanisms of tissue-specific, developmentally- programmed transcription of P450s in the CYP2 family. A variety of experimental approaches were used including in vitro transcription, heterologous promoter transcription assays, transactivation transcription assays, and in vitro DNA binding assays including, gel mobility shift, DNase I footprinting and methylation interference to determine the mechanism of regulation of the CYP2C6, CYP2E1, and CYP2D5 genes. These studies have shown that CYP2C6 promoter is controlled by the liver- enriched transcription factor DBP but is capable of binding to C/EBP- alpha, C/EBP-beta, and DBP. Even though the C/EBP proteins are capable of binding the regulatory region, they cannot activate the CYP2C6 promoter. CYP2E1 is under control of the factor HNF-1-alpha and CYP2D5 is regulated, in part, by Sp1 and C/EBP-beta. CYP7A1, a cholesterol 7- alpha-hydroxylase, is regulated by DBP, C/EBP-alpha, and C/EBP-beta. These data indicate that the developmentally-activated expression of P450 genes in rat liver is due, in part, to the presence and activity of liver-enriched transcription factors.