Pregnane and Xenobiotic Receptor (PXR): a Promiscous Xenosensor in Human Health and Disease


Affiliations

  • Jawaharlal Nehru University, Special Centre for Molecular Medicine, New Delhi, 110067, India
  • University of Michigan Medical Center, Department of Internal Medicine, Ann Arbor, Michigan, 48109, United States

Abstract

Pregnane and Xenobiotic Receptor (PXR) is a member of the nuclear receptor super-family of ligand-regulated transcription factors. Some of its key roles in normal physiological controls and patho-physiological situations are recently becoming more apparent. PXR responds to a large range of chemically distinct endobiotics (steroids, bile acids and their derivatives, vitamins, etc.) and xenobiotics (synthetic drugs, herbal medicines, endocrine disrupters, etc.). As a result of its chemical sensory capabilities and gene modulatory functions in controlling cellular detoxification pathways, PXR has been appropriately termed by some as a 'xenosensor' or 'master regulator'. The present review focuses on two facets of this unique receptor. First, its function in maintaining homeostasis that primarily involves rapid and timely elimination of toxic endogenous metabolites and exogenous chemicals. Second, its involvement in dysregulated metabolic conditions (such as osteomalacia) and certain chronic diseases like cancer. When PXR encounters circumstances that are discordant with normal homeostasis, it orchestrates a response by utilizing and modulating the components of the central detoxification defense machinery, i.e. phase I and phase II drug metabolizing enzymes, as well as drug transporters. The presence of PXR in tissues other than the expected ones (liver and intestine) along with the occurrence of various isoforms (three or more) indicates much more diverse roles for this receptor than previously suspected. The possibility of the presence of various PXR isoforms in different tissues suggests utilization of combinatorial mechanisms to regulate different sets of genes under varied physiological and pathogenic conditions. Further studies are expected to divulge important roles of PXR in drug-drug interactions, development of several metabolic disorders and in designing safer therapeutic molecules.

Keywords

Cancer, Cytochrome P450, Metabolic Disorders, Nuclear Receptor, SXR.

Subject Discipline

Health Care and Hospital Management

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