CAR, The Continuously Advancing Receptor, in Drug Metabolism and Disease

Abstract

The detoxification and elimination of potentially toxic foreign and endogenous compounds depends on the concerted action of xenobiotic metabolizing enzymes. Nuclear hormone receptors (NHRs) have emerged as key regulators of the expression of these enzymes and his review focuses on the xenosenor CAR (Constitutive Androstane Receptor, NR1I3). CAR is highly expressed in the liver and the small intestine, two key tissues expressing xenobiotic metabolizing enzymes, and mediates the induction of their expression by the widely used antiepileptic drug, phenobarbital (PB) and the potent synthetic inducer 1, 4-bis-(2-(3, 5, -dichloropyridyloxy)) benzene (TCPOBOP). TCPOBOP is an agonist ligand for CAR. PB induces its nuclear translocation, which results in increased expression of CAR target genes since, unlike the classical, ligand-dependent nuclear receptors, CAR is an apparently constitutive transactivator. This constitutive activity is inhibited by the inverse agonist ligands androstanol and androstenol. The CAR mediated induction of the expression of xenobiotic metabolizing enzymes is generally protective, but can be deleterious if toxic metabolites are produced. CAR also has a protective role in the stress response elicited by hyperbilirubinemia, as well as lithocholic acid induced cholestasis. In addition, recent studies show that CAR activation disrupts thyroid hormone homeostasis. Finally, CAR activation promotes hepatocyte proliferation and blocks apoptosis, and is essential for the tumorigenesis induced by its activators PB and TCPOBOP. The role of CAR in endobiotic and xenobiotics metabolism has clinical implications in disease prevention, drug-drug interactions, and the development of better drug treatments.

The nuclear receptor CAR modulates alcohol-induced liver injury

“…5,[16][17][18] In this study, we found that ethanol could also increase the expression of CAR target genes CYP2B10 and CYP2E1 via a CAR-dependent manner. However, the increase in the magnitude of CAR activation is not strong as the increase of the target gene expression is not robust.…”

“…What is the reason that only a small population has a higher risk of alcoholic liver diseases? Considering that many prescription drugs and environment contaminants can activate CAR, 5 we propose that the simultaneous exposure to the CAR activators and alcohol consumption may greatly enhance individual susceptibilities to alcohol-induced liver damage.…”

“…4 The major target genes of CAR include cytochrome P450 enzymes such as CYP1A2, CYP2E1, CYP2B10, and CYP3A11. 5 Recent studies also reported that CAR has a role in diabetes mellitus and metabolism of glucose and lipid. 6,7 On the other hand, several nuclear receptors, PPARa, PPARg, PPARd, RAR, and HNF4a, have been shown to be involved in alcohol-induced liver injury.…”

Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3)

“…CAR, upon activation by therapeutics such as PB, induces a large set of genes that encode for drugmetabolizing enzymes with the CYP2B enzymes being the classic CAR-regulated genes, thus increasing hepatic capability for drug metabolism and excretion (2)(3)(4). CAR plays the essential role in PB-induced promotion of hepatocellular carcinoma development (5).…”

“…Two types of CAR activators can translocate CAR into the nucleus; one type, represented by PB, consists of a number of therapeutic drugs that indirectly translocate CAR into the nucleus without any direct binding. The other type includes various xenobiotics, acting as ligands, which directly bind to CAR, such as 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzen (TCPOBOP) and 6-(4-chlorophenyl)imidazo [2,1-b] [1,3]thiazole-5-carbaldehyde O- (3,4-dichlorobenzyl)oxime (CITCO) for mouse and human CARs, respectively (9,10). Regardless of the types, the molecular mechanism of how these activators translocate CAR into the nucleus has been a mystery since CAR was first characterized as a xenobioticactivated nuclear receptor (1).…”