Role of CAR and PXR in xenobiotic sensing and metabolism

Abstract

Introduction: The xenobiotic detoxification system, which protects the human body from external chemicals, comprises drug-metabolizing enzymes and transporters whose expressions are regulated by pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). The progress made in a large number of recent studies calls for a timely review to summarize and highlight these key discoveries.

Areas covered: This review summarizes recent advances in elucidating the roles of PXR and CAR in the xenobiotic detoxification system. It also highlights the progress in understanding the regulation of PXR and CAR activity at the post-translational levels, as well as the structural basis for the regulation of these two xenobiotic sensors.

Expert opinion: Future efforts are needed to discover novel agonists and antagonists with species and isoform selectivity, to systematically understand the regulation of PXR and CAR at multiple levels (transcriptional, post-transcriptional and post-translational levels) in response to xenobiotics exposure, and to solve the structures of the full-length receptors, which will be enabled by improved protein expression and purification techniques and approaches. In addition, more efforts will be needed to validate PXR and CAR as disease-related therapeutic targets and thus expand their roles as master xenobiotic sensors.

Figure 1

Overlapping and distinctive sets of genes regulated by PXR and CAR in xenobiotic detoxification. Upon activation by xenobiotics, PXR and CAR regulate gene expression through PXR responsive element (PXRRE) and the phenobarbital responsive element module (PBREM) in the promoter regions of target genes encoding phase I and II drug-metabolizing enzymes and drug transporters. “?” indicates genes predicted to be regulated by hPXR and hCAR. “*” indicates genes indentified from rodent experiments that need further validation in human system.

Figure 2

The activity of PXR and CAR is regulated by multiple cellular modulators and cellular processes at multiple levels. Standard arrows indicate an activating effect, and blunt arrows indicate an inhibitory effect.

Figure 3

Crystal structure of the hCAR LBD (PDB code 1XV9) and hPXR LBD (PDB code 1ILH). The LBD of PXR (dark blue) and CAR (light blue) were aligned, displaying their respective AF-2 region (pink) and coactivator SRC-1 peptide (green). The β1 and β1′ strands unique in PXR are shown in yellow, and the helix x (H-x) seen in the CAR structure is depicted in red. The complex of CAR LBD with the RXRα LBD (salmon) illustrates a large dimerization interface.