TRANSCRIPTIONAL REGULATION OF CYTOCHROME P450 GENES

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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.