Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450.
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.
Handschin
Christoph
C
Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
Podvinec
Michael
M
Amherd
Remo
R
Looser
Renate
R
Ourlin
Jean-Claude
JC
Meyer
Urs A
UA
D000818:Animals; D030161:Avian Proteins; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D004790:Enzyme Induction / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D010634:Phenobarbital / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015262:Xenobiotics / Q000494:pharmacology*
D030161:Avian Proteins; D001647:Bile Acids and Salts; C414737:CXR protein, chicken; D017931:DNA Primers; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010634:Phenobarbital