Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes

被引:231
作者
Wang, HB [1 ]
LeCluyse, EL [1 ]
机构
[1] Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA
关键词
D O I
10.2165/00003088-200342150-00003
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
During the past several years, important advances have been made in our understanding of the mechanisms that regulate the expression of genes that determine drug clearance, including phase I and phase II drug-metabolising enzymes and drug transporters. Orphan nuclear receptors have been recognised as key mediators of drug-induced changes in both metabolism and efflux mechanisms. In this review, we summarise recent findings regarding the function of nuclear receptors in regulating drug-metabolising and transport systems, and the relevance of these receptors to clinical drug-drug interactions and the development of new drugs. Emphasis is given to two newly recognised 'orphan' receptors (the pregnane X receptor [PXR] and the constitutive androstane receptor [CAR]) and their regulation of cytochrome P450 enzymes, such as CYP3A4, CYP2Cs and CYP2B6; and transporters, such as P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs) and organic anion transporter peptide 2 (OATP2). Although 'cross-talk' occurs between these two receptors and their target sequences, significant species differences exist between ligand-binding and activation profiles for both receptors, and PXR appears to be the predominant or 'master' regulator of hepatic drug disposition in humans. Several important physiological processes, such as cholesterol synthesis and bile acid metabolism, are also tightly controlled by certain ligand-activated orphan nuclear receptors (farnesoid X receptor [FXR] and liver X receptor [LXR]). In general, their ability to bind a broad range of ligands and regulate an extensive array of genes that are involved in drug clearance and disposition makes these orphan receptors attractive targets for drug development. Drugs have the capacity to alter nuclear receptor expression (modulators) and/or serve as ligands for the receptors (agonists or antagonists), and thus can have synergistic or antagonistic effects on the expression of drug-metabolising enzymes and transporters. Coadministration of drugs that are nuclear receptor agonists or antagonists can lead to severe toxicity, a loss of therapeutic efficacy or an imbalance in physiological substrates, providing a novel molecular mechanism for drug-drug interactions.
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页码:1331 / 1357
页数:27
相关论文
共 175 条
[1]   Cholesterol homeostasis: A role for oxysterols [J].
Accad, M ;
Farese, RV .
CURRENT BIOLOGY, 1998, 8 (17) :R601-R604
[2]   IDENTIFICATION AND CHARACTERIZATION OF DNA ELEMENTS IMPLICATED IN THE REGULATION OF CYP4A1 TRANSCRIPTION [J].
ALDRIDGE, TC ;
TUGWOOD, JD ;
GREEN, S .
BIOCHEMICAL JOURNAL, 1995, 306 :473-479
[3]   CLONING OF A PROTEIN THAT MEDIATES TRANSCRIPTIONAL EFFECTS OF FATTY-ACIDS IN PREADIPOCYTES - HOMOLOGY TO PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS [J].
AMRI, EZ ;
BONINO, F ;
AILHAUD, G ;
ABUMRAD, NA ;
GRIMALDI, PA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (05) :2367-2371
[4]   CHRONIC NONHEMOLYTIC UNCONJUGATED HYPERBILIRUBINEMIA WITH GLUCURONYL TRANSFERASE DEFICIENCY - CLINICAL, BIOCHEMICAL, PHARMACOLOGIC AND GENETIC EVIDENCE FOR HETEROGENEITY [J].
ARIAS, IM ;
GARTNER, LM ;
COHEN, M ;
EZZER, JB ;
LEVI, AJ .
AMERICAN JOURNAL OF MEDICINE, 1969, 47 (03) :395-&
[5]  
Auwerx J, 1999, CELL, V97, P161
[6]   Rifampin drastically reduces plasma concentrations and effects of oral midazolam [J].
Backman, JT ;
Olkkola, KT ;
Neuvonen, PJ .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1996, 59 (01) :7-13
[7]   A NEW ORPHAN MEMBER OF THE NUCLEAR HORMONE-RECEPTOR SUPERFAMILY THAT INTERACTS WITH A SUBSET OF RETINOIC ACID RESPONSE ELEMENTS [J].
BAES, M ;
GULICK, T ;
CHOI, HS ;
MARTINOLI, MG ;
SIMHA, D ;
MOORE, DD .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (03) :1544-1552
[8]   Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction [J].
Bertilsson, G ;
Heidrich, J ;
Svensson, K ;
Åsman, M ;
Jendeberg, L ;
Sydow-Bäckman, M ;
Ohlsson, R ;
Postlind, H ;
Blomquist, P ;
Berkenstam, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12208-12213
[9]   SXR, a novel steroid and xenobiotic-sensing nuclear receptor [J].
Blumberg, B ;
Sabbagh, W ;
Juguilon, H ;
Bolado, J ;
van Meter, CM ;
Ono, ES ;
Evans, RM .
GENES & DEVELOPMENT, 1998, 12 (20) :3195-3205
[10]   Orphan nuclear receptors - new ligands and new possibilities [J].
Blumberg, B ;
Evans, RM .
GENES & DEVELOPMENT, 1998, 12 (20) :3149-3155