Department of Molecular and Experimental Medicine
Cytochrome P450: Structure, Function and Regulation
The focus of our research is to understand how the structural diversity and regulation of human cytochrome P450 (CYP) monooxygenases contribute to an individual's ability to avoid the adverse effects of environmental chemicals and affect the metabolism and disposition of therapeutic drugs.
Cytochrome P450 monooxygenases oxidize a large variety of nutritive and non-nutritive lipids including man-made xenobiotics to reduce toxicity and increase their elimination. The expression of individual P450 enzymes is controlled by a variety of hormonal and metabolic inputs as well as by xenobiotics. Our current studies focus on the regulation and function of human CYP4A11 and CYP4F2, which 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 non-human species, significant differences are evident between mammalian species in the number of CYP4 genes and the pathways that govern their expression. Our studies are uncovering mechanisms of human CYP4F2 gene regulation in response to xenobiotics, hormones and nutritional status. Additionally, we are using human CYP4A11 and CYP4F2 transgenes in Cyp4a10 null mice to gauge the effect of expression of each transgene on the susceptibility of the Cyp4a10 null mice to develop salt-sensitive hypertension and to relate these changes to differences in renal and hepatic lipid metabolism, inflammation and gene expression. The underlying mechanisms are likely to contribute to the reported association of genetic variation of the human CYP4A11 and CYP4F2 genes with risks for hypertension and related vascular disorders. These mechanisms are likely to reflect the roles of Cyp4a10, CYP4A11 and CYP4F2 in lipid metabolism with consequent effects on gene regulation that contribute to salt dependent hypertension in mice.
Cytochrome P450 monooxygenases often determine the clearance of candidate drugs limiting their efficacy. These enzymes can also be sources for off-target toxicity. A long term objective is to understand the structural determinants of substrate recognition by P450 enzymes. Collectively and individually the human drug metabolizing P450s can metabolize structurally diverse range of substrates, and this is likely to reflect in part the flexibility of each enzyme and structural adaptations for substrate binding. This underscores the necessity to determine multiple structures of individual enzymes in complex with structurally dissimilar drugs to understand the contribution of conformational flexibility to drug binding. Specific changes in the active site architectures of P450s 1B1, 1A2, 2D6, and 2C19 induced by interaction with chemically diverse substrates, inhibitors and activators, alone or in combination, will be identified to delineate the range of adaptive changes that can occur for each enzyme. Additionally, the active site architectures additional P450s will be determined to identify structural characteristics that control the important functional contribution made by these enzymes to drug metabolism and the clearance of xenobiotics and excess endogenous compounds. Collectively, these studies will address significant gaps in our knowledge of P450 structure as it relates to function, and provide important information and tools for the prediction of drug metabolism. These studies will also provide new information to guide drug design in order to avoid limitations of efficacy and undesirable off-target effects resulting from cytochrome P450 mediated drug metabolism. This will benefit a wide range of therapeutic areas targeted for drug development.
Ph.D., Chemistry, University of Illinois at Urbana-Champaign , 1972
The Bernard B. Brodie Award in Drug Metabolism, American Society for Pharmacology and Experimental Therapeutics
Ronald W. Estabrook, Scientific AchievementAward, International Society for the Study of Xenobiotics
Editor-in-Chief, Drug Metabolism and Disposition; Editorial Board, Molecular Pharmacology