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Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450
Journal
Journal of Biological Chemistry
Volume
277
Number
33
Pages / Article-Number
29561-7
Keywords
Animals; *Avian Proteins; Base Sequence; Bile Acids and Salts/*pharmacology; Cell Line; Cholesterol/*pharmacology; Cytochrome P-450 Enzyme System/*biosynthesis/genetics; DNA Primers; Enhancer Elements (Genetics); Enzyme Induction/*drug effects; Gene Expression Regulation; Enzymologic/drug effects; Humans; Molecular Sequence Data; Phenobarbital/pharmacology; Receptors; Cytoplasmic and Nuclear/metabolism; Retinoic Acid/metabolism; Signal Transduction/*drug effects; Xenobiotics/*pharmacology
Abstract
Cytochromes P450 (CYP) constitute the major enzymatic system for metabolism of xenobiotics. Here we demonstrate that transcriptional activation of CYPs by the drug-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and the chicken xenobiotic receptor (CXR) can be modulated by endogenous cholesterol and bile acids. Bile acids induce the chicken drug-activated CYP2H1 via CXR, whereas the hydroxylated metabolites of bile acids and oxysterols inhibit drug induction. The cholesterol-sensing liver X receptor competes with CXR, pregnane X receptor, or constitutive androstane receptor for regulation of drug-responsive enhancers from chicken CYP2H1, human CYP3A4, or human CYP2B6, respectively. Thus, not only cholesterol 7 alpha-hydroxylase (CYP7A1), but also drug-inducible CYPs, are diametrically affected by these receptors. Our findings reveal new insights into the increasingly complex network of nuclear receptors regulating lipid homeostasis and drug metabolism.
Publisher
American Society for Biochemistry and Molecular Biology
