Beyond CAR and PXR

Authors: Dixit, S. G.; Tirona, R. G.; Kim, R. B.

Source: Current Drug Metabolism, Volume 6, Number 4, August 2005 , pp. 385-397(13)

Publisher: Bentham Science Publishers

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Abstract:

It is becoming increasingly evident that constitutive, induced, and regulated expression of genes important to the drug disposition process such as drug transporters, phase I and II metabolic enzymes are largely under the transcriptional control of certain nuclear receptor (NR) family members. In the past decade, important new insights regarding the role and relevance of ligand-activated nuclear receptors such as such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in terms of their activation by endogenous biochemicals, natural products, as well as synthetic compounds have led to a much better understanding of the xenobiotic-mediated induction process and the clinical relevance of such NRs to drug therapy in general. However, in addition to CAR and PXR, many orphan and adopted orphan NRs have recently been identified as key regulators of drug disposition genes. Indeed, nuclear receptors including farnesoid X receptor, peroxisome proliferator-activated receptor, and hepatocyte nuclear factors (1 agr

, 3 and 4

) exhibit overlapping ligand specificities and regulate multiple gene targets, resulting in tissue- and organ-specific expression of drug disposition genes. In this review, the biology, pathophysiology, and the potential clinical relevance of such NRs to drug disposition and response are discussed.

Keywords: nuclear receptors; gene transcription; phase I metabolism; phase II metabolism; transporters

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200054633907

Affiliations: 1: 572 Robinson Research Building, 23rd Ave. at Pierce Ave., Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.

Publication date: 2005-08-01

More about this publication?

Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

Beyond CAR and PXR

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