TRANSCRIPTIONAL REGULATION OF CYTOCHROME P-450 GENES

P450基因在复杂的控制下。 存在多个层次的监管 这些基因控制着诱导、组织特异性表达和发育- 程序性基因激活 大鼠肝脏作为P450基因的模型 表情 我们一直在研究CYP 2 E1和CYP 2C 6基因， 在肝脏中表达，并在不同的发育阶段被激活。 CYP 2 E1转录在出生后一天内被显著激活， 而CYP 2C 6直到大鼠进入青春期才表达。 遵守一系列管制 体外转录和DNA结合试验，发现CYP 2 E1是 由肝细胞富集转录因子HNF-1 α控制 （肝细胞核因子-1 α），与DNA上游区域结合 CYP 2 E1的转录起始位点。 该因子表示为 在出生前，并在第二个因素的控制下，指定为HNF-4 表明CYP 2 E1是调节级联的一部分。 发现CYP 2C 6基因受肝细胞富集的 转录因子DBP。 发现该因子结合于 血清白蛋白基因，并控制其在成年大鼠的转录。 DBP表达发生在雄性和雌性大鼠青春期开始时， CYP 2C 6的表达。 通过使用反式激活转染 使用CYP 2C 6启动子驱动氯霉素的试验 乙酰转移酶基因和DBP cDNA的控制下， 我们证明了DBP可以激活巨细胞病毒启动子， CYP 2C 6启动子。 重组DBP也能够 特异性结合CYP 2C 6转录上游的DNA片段 启动站点。

P450 genes are under complex control. Several levels of regulation exist that govern inducibility, tissue specific expression and developmentally- programmed gene activation. Rat liver has served as a model for P450 gene expression. We have been studying the CYP2E1 and CYP2C6 genes that are expressed in liver and are activated at distinct stages of development. CYP2E1 transcription is markedly activated within one day after birth, while CYP2C6 is not expressed until rats reach puberty. By a series of in vitro transcription and DNA-binding assays, CYP2E1 was found to be controlled by the hepatocyte-enriched transcription factor HNF-1 alpha (hepatocyte nuclear factor-1 alpha) that binds to a region of DNA upstream of the transcription start site of CYP2E1. This factor is expressed just prior to birth and is under control of a second factor, designated HNF-4 indicating that CYP2E1 is part of a regulatory cascade. The CYP2C6 gene was found to be under control of the hepatocyte-enriched transcription factor DBP. This factor was found to bind to the D site of the serum albumin gene and to control its transcription in adult rats. DBP expression occurs at the onset of puberty in male and female rats as does the expression of CYP2C6. By use of trans-activation transfection assays using the CYP2C6 promoter to drive the chloramphenicol acetyltransferase gene and the DBP cDNA under control of the cytomegalovirus promoter, we demonstrated that DBP could activate tran- scription of the CYP2C6 promoter. Recombinant DBP was also able to specifically bind to a segment of DNA upstream of the CYP2C6 transcription start site.