Minireviews
Nuclear Receptors and Drug Disposition Gene Regulation

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ABSTRACT:

In this minireview, the role of various nuclear receptors and transcription factors in the expression of drug disposition genes is summarized. Specifically, the molecular aspects and functional impact of the aryl hydrocarbon receptor (AhR), nuclear factor-E2 p45-related factor 2 (Nrf2), hepatocyte nuclear factor 1α (HNF1α), constitutive androstane receptor (LAR), pregnane X receptor (PXR), farnesoid X receptor (FXR), peroxisome proliferator-activated receptor α (PPARα), hepatocyte nuclear factor 4α (HNF4α), vitamin D receptor (VDR), liver receptor homolog 1 (LRH1), liver X receptor (LXRα), small heterodimer partner-1 (SHP-1), and glucocorticoid receptor (GR) on gene expression are detailed. Finally, we discuss some current topics and themes in nuclear receptor-mediated regulation of drug metabolizing enzymes and drug transporters. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association

Section snippets

Abbreviations:

    AhR

    aryl hydrocarbon receptor

    CAR

    constitutive androstane receptor

    FXR

    farnesoid X receptor

    GR

    glucocorticoid receptor

    HNF1α

    hepatocyte nuclear factor 1α

    HNF4α

    hepatocyte nuclear factor 4α

    LRH-1

    liver receptor homolog-1

    LXRα

    liver X receptor α

    Nrf2

    nuclear factor-E2 p45-related factor 2

    PPARα

    peroxisome proliferator-activated receptor α

    SHP-1

    small heterodimer partner-1

    VDR

    vitamin D receptor.

INTRODUCTION

The expression of drug metabolizing enzymes and drug transporters in a number of organs and tissues determines local and systemic drug exposure and the resultant pharmacological and toxicological effects. Therefore, interindividual variation in drug response in terms of loss of drug efficacy as well as drug toxicities is often related to variability in the expressed levels of genes involved in the drug disposition process. Among the many mechanisms involved in the regulation of gene expression,

Aryl HYDROCARBON RECEPTOR (AhR)

The AhR was first identified as a receptor for dioxins1 inducing the expression of aryl hydrocarbon hydroxylase (cyp1a) and subsequently cloned2 as a member of the basic helix-loop-helix transcription factors. The well-studied, ligand-dependent transcriptional activation of AhR requires heterodimerization of AhR with the AhR nuclear translocator (ARNT)3 and binding of the complex to xenobiotic response elements (XRE) of target genes. Functional XREs, composed of a core pentanucleotide sequence

NUCLEAR FACTOR-E2 p45-RELATED FACTOR 2 (Nrf2)

Nrf2 is a member of the basic region-leucine zipper proteins, which binds to antioxidant response elements (ARE; 5′-TGACnnnGC-3′) of genes involved in cellular protection against oxidative stress, such as GSTs and NQO1.4,5 Furthermore, drug metabolizing enzymes, such as CYPs,6 UGTs,6 and the efflux transporter, MRP1,7 are regulated by Nrf2. Nrf2 associates with the Kelch-like ECH-related protein, Keap1, in the cytosol, but during oxidative or electrophilic stress, Nrf2 is released from Keap1

HEPATOCYTE NUCLEAR FACTOR 1α (HNF1α)

HNF1α is related to products of homeobox genes and acts as a functional homodimer to regulate genes essential for hepatocyte differentiation.10,11 The importance of HNF1α in hepatic function is demonstrated by murine models whereby gene knockout causes a constellation of pathologies including renal, hepatic dysfunction, cholesterol and bile acid metabolism.12., 13., 14. The expression of drug transporting OATPs14,15 and drug metabolizing CYPs16 and UGTs17,18 are critically dependent on HNF1α

NUCLEAR RECEPTOR FAMILY 1 (NR1)

Members of the NR1 family of transcription factors that impact drug disposition genes include the constitutive androstane receptor (CAR), pregnane X receptor (PXR), farnesoid X receptor (FXR), peroxisome proliferator-activated receptors (PPAR) α and γ, and the vitamin D receptor (VDR). Structurally, members of this transcription factor family consist of a N-terminal activation function (AF-1), a DNA binding domain, a hinge region, a ligand-binding domain, and a C-terminal activation function

Co-Ordinate Nuclear Receptor Control of Gene Transcription

Constitutive and inductive expression of drug disposition genes is under co-ordinate transcriptional control by nuclear receptors. For example, PXR- and CAR-mediated induction of CYP2B,100,101 CYP2C,102 CYP3A,103., 104., 105. and GST102 genes is modulated by GR signaling (Table 1). Moreover, CAR106,107 and PXR104,108,109 expression is enhanced by GR activation. The complexity of co-ordinate nuclear receptor regulation is highlighted in the regulation of CYP3A4 expression. The combined actions

SUMMARY

There has been much progress in our understanding of the transcriptional mechanisms that regulate the expression of drug disposition genes. It is now established that a number of ligand-activated nuclear receptors and transcription factors may be the important determinants of interindividual variability in drug response and toxicity. These advances have directly impacted the drug discovery and development process whereby nuclear receptor activation assays are routinely performed to aid in the

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