LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver.
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.
Gnerre
Carmela
C
Division of Pharmacology/Neurobiology, Biozentrum of the University of Basel, CH-4056 Basel, Switzerland.
Schuster
Gertrud U
GU
Roth
Adrian
A
Handschin
Christoph
C
Johansson
Lisen
L
Looser
Renate
R
Parini
Paolo
P
Podvinec
Michael
M
Robertsson
Kirsten
K
Gustafsson
Jan-Ake
JA
Meyer
Urs A
UA
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
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