CAR and PXR: the xenobiotic-sensing receptors

Abstract

The xenobiotic receptors CAR and PXR constitute two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. This unique function of CAR and PXR sets them apart from the steroid hormone receptors. In contrast, the steroid receptors, exemplified by the estrogen receptor (ER) and glucocorticoid receptor (GR), are the sensors that tightly monitor and respond to changes in circulating steroid hormone levels to maintain body homeostasis. This divergence of the chemical- and steroid-sensing functions has evolved to ensure the fidelity of the steroid hormone endocrine regulation while allowing development of metabolic elimination pathways for xenobiotics. The development of the xenobiotic receptors CAR and PXR also reflect the increasing complexity of metabolism in higher organisms, which necessitate novel mechanisms for handling and eliminating metabolic by-products and foreign compounds from the body. The purpose of this review is to discuss similarities and differences between the xenobiotic receptors CAR and PXR with the prototypical steroid hormone receptors ER and GR. Interesting differences in structure explain in part the divergence in function and activation mechanisms of CAR/PXR from ER/GR. In addition, the physiological roles of CAR and PXR will be reviewed, with discussion of interactions of CAR and PXR with endocrine signaling pathways.

Figure 1. Chemical structures of ligands for CAR and PXR, and the nuclear steroid receptors ER and GR

Each horizontal set of compounds represent the prototypical ligands, respectively from top to bottom, for CAR, PXR, ER and GR.

Figure 2. Summary of signaling pathways for CAR and PXR, and the nuclear steroid receptors ER and GR

Figure 3. Contrasting the functional domain architecture of CAR and PXR to that of the steroid receptors

ERα, representing the steroid receptors, is shown together with human and mouse forms of CAR and PXR. The percent identities in the DBDs and LBDs are shown relative to hCAR.

Figure 4. Comparison of the PXR LBD with bound rifampicin to the apo-PXR LBD

(A) Crystal structure of the Ligand binding domain of human PXR in complex with Rifampicin (green) (pdb idcode 1ILG). (B) Crystal structure of the ligand binding domain of hPXR (orange) in complex with Rifampicin (green) (pdb idcode 1ILG) superimposed with the apo form of the LBD (blue) (pdb idcode 1SKX). Two loops become disordered upon binding Rifampicin (residues 229-235 and 310-317). The position of Leucine residue 209 in the apo form is displaced by Rifampicin in the halo form resulting in residues 198-209 also becoming disordered.