Cytochrome P450 monooxygenases oxidize a large variety of nutritive and non-nutritive lipids including man-made xenobiotics. P450 oxidation often provides the first step in the elimination of troublesome environmental compounds but can also produce teratogenic, toxic or carcinogenic products and generate reactive oxygen species. Conditional regulation of P450 expression can alter the balance between toxication and detoxication of xenobiotics. The expression of individual P450 enzymes is controlled by a variety of hormonal and metabolic inputs as well as by xenobiotics. Current projects focus on the regulation and structure of the human family 4 P450 (CYP4) enzymes. CYP4 enzymes oxidize both endobiotic and xenobiotic substrates and contribute to lipid homeostasis, protection from xenobiotics, and signal transduction pathways regulating hemodynamics and inflammation. Although the regulation of CYP4 gene expression has been characterized in various species, significant differences are evident between species in the number of CYP4 genes and the pathways that regulate them. The unique features of the human CYP4 family need to be identified, and the regulation and function of these enzymes should be evaluated in complex physiologic settings. The proposed studies address mechanisms of human CYP4 gene regulation through the identification of cis-acting control elements and the associated transcription factors that regulate expression of the CYP4A11, CYP4F2 and CYP4Z1 genes in response to xenobiotics, hormones and nutritional status. CYP4A11 and CYP4Z1 transgenic mice will be generated in order to characterize regulatory responses to physiologic alterations that accompany conditions such as pregnancy and fasting. In addition, techniques developed in our laboratory will be applied to the modification, expression and crystallization of representative CYP4 enzymes to identify structural determinants of substrate specificity and their unique capacity to selectively oxidize primary carbon hydrogen bonds. ? ? ?
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