Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR

Abstract

Drug-metabolizing enzymes (DMEs) and transporters play pivotal roles in the disposition and detoxification of numerous foreign and endogenous chemicals. To accommodate chemical challenges, the expression of many DMEs and transporters is up-regulated by a group of ligand-activated transcription factors namely nuclear receptors (NRs). The importance of NRs in xenobiotic metabolism and clearance is best exemplified by the most promiscuous xenobiotic receptors: pregnane X receptor (PXR, NR1I2) and constitutive androstane/activated receptor (CAR, NR1I3). Together, these two receptors govern the inductive expression of a largely overlapping array of target genes encoding phase I and II DMEs, and drug transporters. Moreover, PXR and CAR also represent two distinctive mechanisms of NR activation, whereby CAR demonstrates both constitutive and ligand-independent activation. In this review, recent advances in our understanding of PXR and CAR as xenosensors are discussed with emphasis placed on the differences rather than similarities of these two xenobiotic receptors in ligand recognition and target gene regulation.

Fig. 1

Schematic illustration of the activation mechanisms and target genes of CAR and PXR. CAR can be activated by either direct (ligand binding) or indirect mechanisms, while activation of PXR is purely ligand dependent. CAR and PXR shared target genes are grouped in a red box, CAR-specific targets in a blue box, and PXR-specific targets in a purple box (modified from Qatanani and Moore, Curr. Drug Metab., 2005).

Fig. 2

Expanded xenobiotic responsive elements binding to PXR and CAR. In addition to traditional direct or everted repeats of (A/G)(G/G)GTCA half site spaced by 3, 4 or 6 nucleotides, novel inverted (IR0) and ER8 were identified in the promoter of PXR and CAR target genes.

Fig. 3

CITCO but not PB reactivates PK11195 deactivated constitutive activity of hCAR in HepG2 cells. HepG2 cells were transfected with CYP2B6–2.2 kb reporter and hCAR expression vectors, then treated with different combinations of PK11195, CITCO, or PB at indicated concentrations for 24 h. Luciferase activities were determined and expressed relative to vehicle control (CT). Data represent the mean ± S.D. (n=3) (**, P<0.01 denotes comparison with DMSO group; #, P<0.05, and ##, P<0.01 denote comparison with 10 μM PK11195 group). (Adopted from Li et al., Mol. Pharmacol. 2008).