Our long-range objectives are to characterize the regulation and function of cytochrome P450 monooxygenases. These enzymes metabolize a large variety of lipid soluble xenobiotics as well as endogenous compounds such as steroids, prostaglandins, and fatty acids. The expression of individual P450 enzymes is controlled by a variety of hormonal factors, and specific P450s can be induced by xenobiotics. In many cases, the induction of these enzymes provides a means to increase the detoxication of xenobiotics or the degradation of endogenous lipids, steroids, and sterols. However, some of the ligand activated transcription factors that mediate these responses can also elicit pathological responses that lead to toxicity and carcinogenesis. These responses often vary between species, and the mechanisms leading to these negative outcomes are poorly understood. The present studies seek to delineate the mechanisms that underlie the regulation of P450 gene expression by xenobiotics and endobiotics. The specific alms focus on the regulation of family 4 P450s by ligand activated transcription factors such as the peroxisome proliferator activated receptor (PPAR), the pregnane x receptor (PXR), and other nuclear receptors. (1) Human genes that are regulated by peroxisome proliferators will be identified, and the impact of quantitative differences in PPAR expression between human and mouse will be examined to determine if this underlies the differences in the pathological effects of peroxisome proliferators observed between these species. (2) Additional human family 4 P450s will be characterized, and their potential regulation by nuclear receptors will be determined. (3) Mechanisms leading to the elevated expression of P450 4A4 during pregnancy, and the role of PXR or related nuclear receptors in this process, will be examined by identifying response elements and characterizing the roles of specific transcription factors in the regulation of this gene.
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