Enhancement of Glucuronide-Conjugating Capacity in a Hyperbilirubinemic Infant Due to Apparent Enzyme Induction by Phenobarbital

Yaffe, Sumner J.; Levy, Gerhard; Matsuzawa, Tai; Baliah, Tadla

doi:10.1056/nejm196612292752602

Cited by 250 publications

(30 citation statements)

References 14 publications

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“…The first implication that CAR might play an important role in bilirubin detoxification came from the fact that PB, a strong CAR activator, is clinically effective in treating hyperbilirubinemia [65]. All the genes involved in the clearance pathway have been shown to be regulated by CAR, and their induction when serum bilirubin is elevated is an adaptive response that can protect the organism from this harmful metabolic byproduct [24,53,66,67].…”

Section: Car and Jaundicementioning

confidence: 99%

CAR, The Continuously Advancing Receptor, in Drug Metabolism and Disease

Qatanani¹,

Moore²

2005

CDM

157

134

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The detoxification and elimination of potentially toxic foreign and endogenous compounds depends on the concerted action of xenobiotic metabolizing enzymes. Nuclear hormone receptors (NHRs) have emerged as key regulators of the expression of these enzymes and his review focuses on the xenosenor CAR (Constitutive Androstane Receptor, NR1I3). CAR is highly expressed in the liver and the small intestine, two key tissues expressing xenobiotic metabolizing enzymes, and mediates the induction of their expression by the widely used antiepileptic drug, phenobarbital (PB) and the potent synthetic inducer 1, 4-bis-(2-(3, 5, -dichloropyridyloxy)) benzene (TCPOBOP). TCPOBOP is an agonist ligand for CAR. PB induces its nuclear translocation, which results in increased expression of CAR target genes since, unlike the classical, ligand-dependent nuclear receptors, CAR is an apparently constitutive transactivator. This constitutive activity is inhibited by the inverse agonist ligands androstanol and androstenol. The CAR mediated induction of the expression of xenobiotic metabolizing enzymes is generally protective, but can be deleterious if toxic metabolites are produced. CAR also has a protective role in the stress response elicited by hyperbilirubinemia, as well as lithocholic acid induced cholestasis. In addition, recent studies show that CAR activation disrupts thyroid hormone homeostasis. Finally, CAR activation promotes hepatocyte proliferation and blocks apoptosis, and is essential for the tumorigenesis induced by its activators PB and TCPOBOP. The role of CAR in endobiotic and xenobiotics metabolism has clinical implications in disease prevention, drug-drug interactions, and the development of better drug treatments.

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Section: Car and Jaundicementioning

confidence: 99%

CAR, The Continuously Advancing Receptor, in Drug Metabolism and Disease

Qatanani¹,

Moore²

2005

CDM

157

134

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“…It is possible that induction of cholinesterase in epileptic patients treated with phenobarbital contributes to the changes in lipid levels [138]. Beneficial effects of phenobarbital on hyperbilirubinemia [139] and of phenobarbital and rifampicin on cholestasis [140] have been observed for decades. Recently, the xenosensors PXR and CAR have been identified to mediate at least some of these therapeutic effects [50,51,57,141].…”

Section: Experimental and Clinical Observationsmentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

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“…It has long been known that phenobarbital (PB), a well studied inducer of drug metabolism, can increase bilirubin-conjugating activity and decrease elevated bilirubin levels in humans (6,7).…”

mentioning

confidence: 99%

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

Huang

Zhang

Chua

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

361

268

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Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. Because the nuclear hormone receptor constitutive androstane receptor (CAR) mediates hepatic effects of this xenobiotic inducer, we hypothesized that CAR could be a regulator of bilirubin clearance. Activation of the nuclear hormone receptor CAR increases hepatic expression of each of five components of the bilirubin-clearance pathway. This induction is absent in homozygous CAR null mice but is observed in mice expressing human CAR instead of mouse CAR. Pretreatment with xenobiotic inducers markedly increases the rate of clearance of an exogenous bilirubin load in wild-type but not CAR knockout animals. Bilirubin itself can also activate CAR, and mice lacking CAR are defective in clearing chronically elevated bilirubin levels. Unexpectedly, CAR expression is very low in livers of neonatal mice and humans. We conclude that CAR directs a protective response to elevated bilirubin levels and suggest that a functional deficit of CAR activity may contribute to neonatal jaundice

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Enhancement of Glucuronide-Conjugating Capacity in a Hyperbilirubinemic Infant Due to Apparent Enzyme Induction by Phenobarbital

Cited by 250 publications

References 14 publications

CAR, The Continuously Advancing Receptor, in Drug Metabolism and Disease

CAR, The Continuously Advancing Receptor, in Drug Metabolism and Disease

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Induction of bilirubin clearance by the constitutive androstane receptor (CAR)

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