PXR antagonists and implication in drug metabolism

Abstract

Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application.

Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity

“…In colon cancer cells, expression of wild-type p53 induces apoptosis (Shaw et al, 1992), whereas activation of PXR induces colon tumor growth and malignancy (Wang et al, 2011;Mani et al, 2013;Pondugula and Mani, 2013). In this study, we showed that in colon cancer cell line HCT116, wildtype p53 downregulates PXR activity.…”

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

“…Similar to the AhR, the pregnane X receptor (PXR) can bind and be activated by a structurally diverse collection of ligands. The results of 3-dimensional protein structure analysis of PXR ligand binding has revealed that the dramatic structural promiscuity of PXR ligands can be explained by the characteristics of its binding pocket, which allows structurally diverse ligands to bind in a variety of different orientations and positions within the PXR LBD (28)(29)(30). By analogy, the structural diversity of AhR ligands may also result from differential interactions of ligands or classes of ligands with different residues within the AhR LBD (1,2).…”

Alisol B 23-acetate promotes liver regeneration in mice after partial hepatectomy via activating farnesoid X receptor

“…Nuclear receptors are involved in the modulation of hepatocyte priming and proliferation [25]. In addition to FXR, PXR is another nuclear receptor in liver, which is also essential for normal progression of liver regeneration [30,31]. Therefore, we investigated the involvement of PXR in the AB23A-induced liver regeneration promotion.…”