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

• DOI: 10.1124/dmd.113.053850
• Publication Date: 2013-11-06T03:16:15Z
• Authors: Pranav Shah; Tao Guo; David D Moore; Romi Ghose
• Keywords: Lipopolysaccharides; Male; 0301 basic medicine; Receptors, Steroid; Cytoplasmic and Nuclear; 1.1 Normal biological development and functioning; Down-Regulation; Gene Expression; Receptors, Cytoplasmic and Nuclear; Inbred C57BL; Inactivation; Mice; 03 medical and health sciences; Cytochrome P-450 Enzyme System; Underpinning research; Receptors; Genetics; Animals; Pharmacology & Pharmacy; Glucuronosyltransferase; Steroid; Constitutive Androstane Receptor; Biomedical and Clinical Sciences; Liver Disease; Prevention; Toll-Like Receptors; Pregnane X Receptor; Membrane Transport Proteins; Biological Transport; Pharmacology and Pharmaceutical Sciences; 3. Good health; Mice, Inbred C57BL; Teichoic Acids; Pharmacology and pharmaceutical sciences; Liver; Inactivation, Metabolic; Hepatocytes; Metabolic; Digestive Diseases

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.