Regulation of P450 genes by liver-enriched transcription factors and nuclear receptors

Abstract Cytochrome P450s (P450s) constitute a superfamily of heme-proteins that play an important role in the activation of chemical carcinogens, detoxification of numerous xenobiotics as well as in the oxidative metabolism of endogenous compounds such as steroids, fatty acids, prostaglandins, and leukotrienes [FASEB J. 10 (1996) 1112; DNA Cell Biol. 10 (1991) 1; Pharmacol. Rev. 40 (1988) 243; Crit. Rev. Biochem. Mol. Biol. 25 (1990) 97] . In addition, some P450s have important roles in physiological processes, such as steroidogenesis and the maintenance of bile acid and cholesterol homeostasis [Science 294 (2001) 1866; Cell 103 (2000) 1] . Given their importance, the molecular mechanisms of P450 gene regulation have been intensely studied. Direct interactions between transcription factors, including nuclear receptors, with the promoters of P450 genes represent one of the primary means by which the expression of these genes is controlled. In this review, several liver-enriched transcription factors that play a role in the tissue-specific, developmental, and temporal regulation of P450s are discussed. In addition, the nuclear receptors that play a role in the fine control of cholesterol and bile acid homeostasis, in part, through their modulation of specific P450s, are discussed.