TRANSCRIPTIONAL REGULATION OF CYTOCHROME P450 GENES

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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.