Elsevier

Biochemical Pharmacology

Volume 77, Issue 4, 15 February 2009, Pages 689-699
Biochemical Pharmacology

Coordinate regulation of human drug-metabolizing enzymes, and conjugate transporters by the Ah receptor, pregnane X receptor and constitutive androstane receptor

https://doi.org/10.1016/j.bcp.2008.05.020Get rights and content

Abstract

Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors suggests that these proteins evolved to an integrated biotransformation system. Two major groups of ligand-activated nuclear receptors/xenosensors evolved: the Ah receptor (activated by aryl hydrocarbons and drugs such as omeprazole) and type 2 steroid receptors such as PXR and CAR, activated by drugs such as rifampicin, carbamazepin and phenytoin. It is increasingly recognized that there is considerable cross-talk between these xenosensors. Therefore, an attempt was made to discuss biotransformation by the Ah receptor together with that of PXR and CAR. Due to considerable species differences the emphasis is on human biotransformation. Agonists coordinately induce biotransformation due to common xenosensor-binding response elements in the regulatory region of target genes. However, whereas different groups of xenobiotics appear to more selectively stimulate CYPs (Phase I), their regulatory control largely converged in modulating Phase II metabolism and transport. Biotransformation appears to be tightly controlled to achieve efficient homeostasis of endobiotics and detoxification of dietary phytochemicals, but nuclear receptor agonists may also lead to potentially harmful drug interactions.

Introduction

It is increasingly recognized that cascades of Phase I and II enzymes and transporters act together to protect the body against the accumulation of potentially harmful lipid-soluble compounds. In addition to polymorphisms in the coding region, interindividual levels and activities of the involved proteins are largely determined by complex transcriptional control including actions of xenosensors such as the Ah receptor (AHR) [1], [2], CAR (NR1I3) and PXR (NR1I2) [2], [3], [4], [5], [6], [7]. Notably, these nuclear receptors act as multifunctional switches; for example, the AHR is involved in organ development in addition to adaptive regulation of detoxification. Previously, coordinate regulation of Phase I and II enzymes by AHR and Nrf2 has been discussed, the latter transcription factor controlling a gene battery involved in protection against oxidative stress [8]. However, due to extensive cross-talk between AHR, CAR and PXR, it seemed desirable to discuss their regulation and impact on drug metabolism and transport together; for example, the AHR appears to be a target gene of PXR [4], and CAR may be regulated by the AHR [9]. They belong to different gene superfamilies; the AHR is a member of the basic helix–loop–helix PAS (Per-Arnt-Sim) family [1] whereas PXR and CAR are type 2 members of the steroid receptor family characterized by heterodimerization with the common partner RXR (NR2B1/2/3) [7]. CAR/PXR and the AHR are the key mediators of the classic phenobarbital- and 3-methylcholanthrene-type induction of microsomal drug metabolism, respectively [10], [11], [12]. The genetic basis for coordinate expression of enzymes and transporters is represented in part by common DNA binding motifs present in the regulatory region of target genes. Evolution of common binding motifs hints to considerable functional advantages for the mammalian organism by coordinate regulation of Phase I and II metabolism and transport. It is noteworthy that – in addition to up- and downregulation of target genes – these receptors also regulate basal expression of proteins [13]. Furthermore, the receptors are again under the hierarchical control of regulators [14].

Accumulating evidence suggests considerable species differences in the regulation of biotransformation between rodents and humans. Therefore, the present commentary focuses on human drug metabolism and transport. Hepatic and intestinal CYPs and UGTs as major Phase I and II enzymes together with conjugate uptake and efflux transporters are emphasized to eventually be able to compare regulatory mechanisms with pharmacokinetic data on the bioavailability of drugs and their enterohepatic circulation. Phase II metabolism necessitates transport of the resulting polar conjugates out of cells. These export transporters have been subsummized as Phase III. Conjugates can also be taken up into cells, for example, into hepatoctes for biliary excretion; these uptake processes have been termed Phase 0.

Interestingly, xenobiotic metabolizing enzymes, conjugate transporters as well as their xenosensors are also involved in biotransformation of endobiotics including bile acids, bilirubin, and thyroxin [2], [5], [6], [15]. Expectedly, transcriptional regulatory coupling between these enzymes and transporters is tight in homeostatic control of endobiotics. Conceivably, coupling was also shaped by detoxification of dietary phytochemicals and ubiquitous contaminants to which organisms were exposed in evolution for millions of years [16]. Newly discovered drugs are accidentally handled by the same biotransformation system. The perception that drug metabolism uses an evolved biotransformation or detoxification system, may facilitate understanding of multiple interactions between endo- and xenobiotics. In the following, a brief overview of Phase I and II enzymes and of uptake and export transporters (Phases 0 and III, respectively) is given; subsequently, examples for coordinate transcriptional regulation of these proteins by nuclear receptors are discussed (Table 1). Finally, functional aspects are summarized.

Section snippets

Phase I enzymes

CYPs (cytochrome P450 enzymes) are major Phase I enzymes, encoded by a large supergene family [16], [17]. Known AHR-controlled CYPs are CYP1A1, CYP1A2 and CYP1B1. Basal expression of CYP1A1 is low, but it is markedly inducible by the AHR in hepatocytes, intestinal epithelium and in vascular endothelium. It is involved in both bioactivation of the carcinogen benzo[a]pyrene and in its first-pass detoxification in the intestinal epithelium [18]. CYP1A2 is constitutively expressed in liver but is

Coordinate regulation of drug biotransformation by AHR, CAR and PXR

Coordinate transcriptional regulation of biotransformation enzymes and transporters appears to enhance the efficiency of homeostatic control of endobiotics and detoxification of dietary xenobiotics.

Functional implications of coordinate regulation

An integrated view of biotransformation is necessary when dealing with in vivo functions. For example, under physiological conditions bile acids are mainly conjugated by sulfation. Under cholestatic conditions, however, bile acid sulfation may be saturated and glucuronidation is taking over. ‘Tight coupling’ of Phase I and II metabolism and conjugate transport by nuclear receptors can be expected in homeostasis and detoxification of endobiotics such as bile acids and bilirubin. To some extent

Conclusions

Coordinate regulation of Phase I and II drug-metabolizing enzymes and conjugate transporters by nuclear receptors PXR, CAR and AHR suggests that these proteins evolved to an integrated biotransformation system. The genetic basis for coordinate regulation may be largely due to common nuclear receptor-binding elements in the regulatory region of target genes. Previously, the AHR gene battery and its linkage with the Nrf2 gene battery was discussed, the latter protecting against oxidative stress

Acknowledgements

We thank Dietrich Keppler (DKFZ Heidelberg, Germany) for critical discussions, and apologize for often citing reviews instead of original studies to reduce the number of references.

References (98)

  • D. Keppler

    Uptake and efflux transporters for conjugates in human hepatocytes

    Methods Enzymol

    (2005)
  • A. Geick et al.

    Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampicin

    J Biol Chem

    (2001)
  • S.A. Kliewer et al.

    An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

    Cell

    (1998)
  • V. Radjendirane et al.

    Antioxidant response element-mediated 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induction of human NADP(H):quinone oxidoreductase 1 gene expression

    Biochem Pharmacol

    (1999)
  • M.F. Yueh et al.

    Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1

    J Biol Chem

    (2003)
  • J. Sugatani et al.

    Regulation of the human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnane X receptor, and glucocorticoid receptor

    Methods Enzymol

    (2005)
  • P.A. Münzel et al.

    Contribution of the Ah receptor to phenolic antioxidant-mediated expression of human and rat UDP-glucuronosyltransferase UGT1A6 in Caco-2 and rat hepatoma 5L cells

    Biochem Pharmacol

    (2003)
  • O. Barbier et al.

    The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor α and γ target gene

    J Biol Chem

    (2003)
  • H.R. Kast et al.

    Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor

    J Biol Chem

    (2002)
  • T. Takada et al.

    Characterization of the 5′-flanking region of human MRP3

    Biochem Biophys Res Commun

    (2000)
  • H. Wang et al.

    A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression

    J Biol Chem

    (2003)
  • M.F. Yueh et al.

    Nrf2-Keap1 signaling pathway regulates human UGT1A1 expression in vitro and in transgenic UGT1 mice

    J Biol Chem

    (2007)
  • J. Sugatani et al.

    Identification of a defect in the UGT1A1 promoter and its association with hyperbilirubinemia

    Biochem Biophys Res Commun

    (2002)
  • P.A. Gregory et al.

    Regulation of UDP glucuronosyltransferases in the gastrointestinal tract

    Toxicol Appl Pharmacol

    (2004)
  • H. Wietholtz et al.

    Stimulation of bile acid 6-alpha-hydroxylation by rifampin

    J Hepatol

    (1996)
  • C. Köhle et al.

    Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians

    Biochem Pharmacol

    (2003)
  • C. Köhle et al.

    Activation of coupled Ah receptor and Nrf2 gene batteries by dietary phytochemicals in relation to chemoprevention

    Biochem Pharmacol

    (2006)
  • D. Nebert et al.

    Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture

    J Biol Chem

    (1968)
  • F. Ruschitzka et al.

    Acute heart transplant rejection due to Saint John's wort

    Lancet

    (2000)
  • M.F. Fromm et al.

    Loss of analgesic effect of morphine due to coadministration of rifampicin

    Pain

    (1997)
  • R. Wolbold et al.

    Sex as a major factor of CYP3A4 expression in human liver

    Hepatology

    (2003)
  • S. Gerbal-Chaloin et al.

    Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide

    Cell Signal

    (2006)
  • Y.Z. Gu et al.

    The PAS superfamily: sensors of environmental and developmental signals

    Annu Rev Pharmacol Toxicol

    (2000)
  • J.M. Pascussi et al.

    The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences

    Annu Rev Pharmacol Toxicol

    (2008)
  • J.M. Maglich et al.

    Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification

    Mol Pharmacol

    (2002)
  • E.S. Tien et al.

    Nuclear receptors CAR and PXR in the regulation of hepatic metabolism

    Xenobiotica

    (2006)
  • R.D. Patel et al.

    Aryl hydrocarbon receptor activation regulates constitutive androstane levels in murine and human liver

    Hepatology

    (2007)
  • A. Conney et al.

    The metabolism of methylated amino azodyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene

    Cancer Res

    (1956)
  • H. Remmer

    Die Beschleunigung des Evipanabbaues unter der Wirkung von Barbituraten

    Naturwissenschaften

    (1958)
  • H. Remmer et al.

    Drug-induced changes in the liver endoplasmic reticulum: association with drug-metabolizing enzymes

    Science

    (1963)
  • N. Tijet et al.

    Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries

    Mol Pharmacol

    (2006)
  • W. Xie et al.

    Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor

    Proc Natl Acad Sci USA

    (2003)
  • D.W. Nebert et al.

    P450 genes: structure, evolution and regulation

    Annu Rev Biochem

    (1987)
  • D.R. Nelson et al.

    P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature

    Pharmacogenetics

    (1996)
  • D.L. Eaton et al.

    Role of cytochrome P4501A2 in chemical carcinogenesis: implications for human variability in expression and enzyme activity

    Pharmacogenetics

    (1995)
  • S.S. Ferguson et al.

    Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site

    Mol Pharmacol

    (2002)
  • T. Shimada et al.

    Interindividual variations in liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians

    J Pharmacol Exp Ther

    (1994)
  • V. Özdemir et al.

    Evaluation of the genetic component in CYP3A4 activity: a repeated drug administration method

    Pharmacogenetics

    (2000)
  • L. Wojnowski et al.

    Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa

    Pharmacogenetics

    (2004)
  • Cited by (132)

    • Receptors and drug-metabolizing enzymes: From function to regulation

      2022, Biochemistry of Drug Metabolizing Enzymes: Trends and Challenges
    View all citing articles on Scopus
    View full text