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 In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold.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.

Keywords::

• Pregnane x receptor
• antagonist
• pharmcophore
• drug metabolism
• adverse drug interactions

Acknowledgments

The authors thank Drs. Matthew Redinbo (University of North Carolina, Chapel Hill, North Carolina, USA), Sean Ekins, Sandhya Kortagere (Drexel University, Philadelphia, Pennsylvania, USA), and current and past members of the Mani Laboratory for their contributions toward this project as well as their critical comments on the review. Special thanks are due to Matthew Redinbo for the figures not previously present in the literature.

Declaration of interest

Funding for work presented in this review came from the Albert Einstein Cancer Center (Albert Einstein College of Medicine, Bronx, New York, USA) as well as grants from the National Institutes of Health (CA 127231) and the Damon Runyon Foundation Clinical Investigator Award (CI15-02, and National Natural Science Foundation of China (81150040, 81273572)).