Targeting xenobiotic receptors PXR and CAR in human diseases

Abstract

Nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenobiotic receptors regulating not only drug metabolism and disposition but also various human diseases such as cancer, diabetes, inflammatory disease, metabolic disease and liver diseases, suggesting that PXR and CAR are promising targets for drug discovery. Consequently, there is an urgent need to discover and develop small molecules that target these PXR- and/or CAR-mediated human-disease-related pathways for relevant therapeutic applications. This review proposes approaches to target PXR and CAR, either individually or simultaneously, in the context of various human diseases, taking into consideration the structural differences between PXR and CAR.

Figure 1

Major human diseases involving pregnane X receptor (PXR) or constitutive androstane receptor (CAR). Various proteins can regulate PXR-mediated signaling pathways and thereby contribute to human diseases. PXR and CAR also regulate drug metabolism. (a) PXR activation can suppress the expression of nuclear factor (NF)-κB proinflammatory target genes interleukin (IL)-2, cyclooxygenase (COX)-2, and tumor necrosis factor (TNF)-α. Inversely, activation of NF-κB signaling and the presence of NF-κB-regulated proinflammatory mediators can suppress gene expression mediated by PXR [37]. (b) PXR activation leads to transcriptional upregulation of cytochrome P450 (CYP)3A4 and/or multidrug resistance protein (MDR)1, potentially contributing to chemoresistance [22,45]; however, PXR-mediated transcriptional upregulation of fibroblast growth factor (FGF19) can promote tumor progression, thus contributing to cancer development [46]. (c) CAR can bind to the antiapoptotic protein growth arrest and DNA-damage-inducible beta (GADD45B) to suppress apoptosis and contribute to cancer development [54]. Arrows indicate activation, stop bars indicate suppression.

Figure 2

Major human diseases involving constitutive androstane receptor (CAR) and pregnane X receptor (PXR). Various proteins can regulate CAR and PXR-mediated signaling pathways and thereby contribute to human diseases. PXR and CAR also regulate drug metabolism. CAR and PXR activation has been shown to be modulated by inflammation. (a) The presence of inflammatory mediators such as interleukin (IL)-6 significantly reduces the expression of PXR and CAR and their target genes [38,57]. IL-6 contributes to inflammatory disease. (b) CAR and PXR activation can downregulate gluconeogenesis-associated genes via crosstalk between CAR, PXR and the transcription factor forkhead box protein O1 (FOXO1), as proposed by Kodama et al. [40]. FOXO1 is suppressed in the presence of insulin. FOXO1 is a co-activator of CAR and PXR. Inversely, CAR and PXR can repress FOXO1 activity, reducing the expression of FOXO1-mediated downstream targets providing further insight into the role of CAR in regulating metabolic diseases [40]. Arrows indicate activation, stop bars indicate suppression.

Figure 3

Structural analysis of human pregnane X receptor (PXR) and human constitutive androstane receptor (CAR) ligand-binding domain (LBD). (a) X-ray crystal structure of PXR LBD with bound rifampicin (cyan surface) (PDB: 1SKX). (b) Residues of PXR LBD important for binding to rifampicin (cyan) are shown. (c) X-ray crystal structure of CAR LBD with bound CITCO (cyan surface) (PDB: 1XVP). (d) Residues of CAR important for binding to CITCO (cyan) are shown. Figure 3 was prepared using MOE software.

Figure 4. Pregnane X receptor

(PXR)- and constitutive androstane receptor (CAR) -targeted drug discovery process. The proposed process involves the identification and validation of PXR and CAR as drug targets, the discovery and development of modulators of PXR and CAR, preclinical studies and clinical trials.