LXR deficiency and cholesterol feeding affect expression and phenobarbital mediated induction of cytochromes P450 in mouse liver

Carmela Gnerre, Gertrud U Schuster, Adrian Roth, Christoph Handschin, Lisen Johansson, Renate Looser, Paolo Parini, Michael Podvinec, Kirsten Robertsson, Jan-Ake Gustafsson, and Urs A. Meyer

Pharmacology/Neurobiology, University of Basel, Basel 4056

Corresponding Author: Urs-A.Meyer{at}unibas.ch

Metabolic transformation by the superfamily of cytochromes P450 (CYP) 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 adaptative 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. In order to study the link between LXR, cholesterol homeostasis and drug induction in vivo, we designed experiments in wild-type, LXR $alpha$ , LXR $beta$ or LXR $alpha$ / $beta$ 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, while the absence of LXR leads to an increase in PB-mediated activation of Cyp2b10.

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