title: LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver.
abstract: Metabolic transformation by the superfamily of cytochromes P450 (CYPs) plays an important role in the detoxification of xenobiotics such as drugs, environmental pollutants, and food additives. Endogenous substrates of CYPs include fatty acids, sterols, steroids, and bile acids. Induction of CYPs via transcriptional activation by substrates and other xenobiotics is an important adaptive mechanism that increases the organism's defense capability against toxicity. Numerous in vivo and in vitro data have highlighted the concept that the molecular mechanism of hepatic drug induction is linked to endogenous regulatory pathways. In particular, in vitro data suggest that oxysterols via the liver X receptor (LXR) inhibit phenobarbital (PB)-mediated induction of CYPs. To study the link between LXR, cholesterol homeostasis, and drug induction in vivo, we designed experiments in wild-type, LXRalpha-, LXRbeta-, and LXRalpha/beta-deficient mice. Our data expose differential regulatory patterns for Cyp2b10 and Cyp3a11 dependent on the expression of LXR isoforms and on challenge of cholesterol homeostasis by excess dietary cholesterol. Our results suggest that, in the mouse, liver cholesterol status significantly alters the pattern of expression of Cyp3a11, whereas the absence of LXR leads to an increase in PB-mediated activation of Cyp2b10.
authors.affiliation: Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Carmela
authors.initials: C
authors.lastname: Gnerre
authors.forename: Gertrud U
authors.initials: GU
authors.lastname: Schuster
authors.forename: Adrian
authors.initials: A
authors.lastname: Roth
authors.forename: Christoph
authors.initials: C
authors.lastname: Handschin
authors.forename: Lisen
authors.initials: L
authors.lastname: Johansson
authors.forename: Renate
authors.initials: R
authors.lastname: Looser
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Michael
authors.initials: M
authors.lastname: Podvinec
authors.forename: Kirsten
authors.initials: K
authors.lastname: Robertsson
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Urs A
authors.initials: UA
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002784:Cholesterol / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010634:Phenobarbital / Q000494:pharmacology*; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*; D013250:Steroid Hydroxylases / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D008565:Membrane Proteins; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D010634:Phenobarbital