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Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

Authors :
Shah, Pranav
Guo, Tao
Moore, David D.
Ghose, Romi
Source :
Drug Metabolism and Disposition; 2014, Vol. 42 Issue: 1 p172-181, 10p
Publication Year :
2014

Abstract

Impairment of drug disposition in the liver during inflammation has been attributed to downregulation of gene expression of drug-metabolizing enzymes (DMEs) and drug transporters. Inflammatory responses in the liver are primarily mediated by Toll-like receptors (TLRs). We have recently shown that activation of TLR2 or TLR4 by lipoteichoic acid (LTA) and lipopolysaccharide (LPS), respectively, leads to the downregulation of gene expression of DMEs/transporters. However, the molecular mechanism underlying this downregulation is not fully understood. The xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), regulate the expression of DMEs/transporter genes. Downregulation of DMEs/transporters by LTA or LPS was associated with reduced expression of PXR and CAR genes. To determine the role of CAR, we injected CAR+/+and CAR−/−mice with LTA or LPS, which significantly downregulated (∼40%–60%) RNA levels of the DMEs, cytochrome P450 (Cyp)3a11, Cyp2a4, Cyp2b10, uridine diphosphate glucuronosyltransferase 1a1, amine N-sulfotransferase, and the transporter, multidrug resistance-associated protein 2, in CAR+/+mice. Suppression of most of these genes was attenuated in LTA-treated CAR−/−mice. In contrast, LPS-mediated downregulation of these genes was not attenuated in CAR−/−mice. Induction of these genes by mouse CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene was sustained in LTA- but not in LPS-treated mice. Similar observations were obtained in humanized CAR mice. We have replicated these results in primary hepatocytes as well. Thus, LPS can downregulate DME/transporter genes in the absence of CAR, whereas the effect of LTA on these genes is attenuated in the absence of CAR, indicating the potential involvement of CAR in LTA-mediated downregulation of DME/transporter genes.

Details

Language :
English
ISSN :
00909556 and 1521009X
Volume :
42
Issue :
1
Database :
Supplemental Index
Journal :
Drug Metabolism and Disposition
Publication Type :
Periodical
Accession number :
ejs31695870
Full Text :
https://doi.org/10.1124/dmd.113.053850