Pregnane X receptor mediates the induction of P-glycoprotein by spironolactone in HepG2 cells
Juan Pablo RigalliMaría Laura RuizVirginia PerdomoSilvina Stella Maris VillanuevaAldo D. MottinoViviana A. Catania
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Keywords:
Pregnane X receptor
P-glycoprotein
Constitutive androstane receptor
Rhodamine 123
Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are members of the nuclear receptor superfamily. These transcription factors are predominantly expressed in the liver, where they are activated by structurally diverse compounds, including many drugs and endogenous substances. CAR and PXR regulate the expression of a broad range of genes, which contribute to transcellular transport, bioactivation, and detoxification of numerous xenochemicals and endogenous substances. This article discusses the importance of these receptors for pharmacology and toxicology, emphasizing the role of individual drugs and natural products as agonists, indirect activators, inverse agonists, and antagonists of CAR and PXR.
Pregnane X receptor
Constitutive androstane receptor
Pregnane
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The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are closely related orphan nuclear hormone receptors that play a critical role as xenobiotic sensors in mammals. Both receptors regulate the expression of genes involved in the biotransformation of chemicals in a ligand-dependent manner. As the ligand specificity of PXR and CAR have diverged between species, the prediction of in vivo PXR and CAR interactions with a drug are difficult to extrapolate from animals to humans. We report the development of what we believe are novel PXR- and CAR-humanized mice, generated using a knockin strategy, and Pxr- and Car-KO mice as well as a panel of mice including all possible combinations of these genetic alterations. The expression of human CAR and PXR was in the predicted tissues at physiological levels, and splice variants of both human receptors were expressed. The panel of mice will allow the dissection of the crosstalk between PXR and CAR in the response to different drugs. To demonstrate the utility of this panel of mice, we used the mice to show that the in vivo induction of Cyp3a11 and Cyp2b10 by phenobarbital was only mediated by CAR, although this compound is described as a PXR and CAR activator in vitro. This panel of mouse models is a useful tool to evaluate the roles of CAR and PXR in drug bioavailability, toxicity, and efficacy in humans.
Pregnane X receptor
Constitutive androstane receptor
Humanized mouse
Pregnane
Xenobiotic
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Pregnane X receptor
Constitutive androstane receptor
Xenobiotic
Pregnane
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Aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor-α (PPARα), and nuclear factor-E2-related factor 2 (Nrf2) are transcription factors that mediate xenobiotic induction of biotransformation enzymes and transporters. The purpose of this study was to determine the tissue distribution and xenobiotic induction of these transcription factors and their associated target genes in mice. Many of these transcription factors were most highly expressed in extrahepatic tissues. CAR expression in female liver was twice that in male liver. This corresponded with greater induction of the CAR target genes Cyp2b10 and multidrug resistance-associated protein (Mrp) 4 by the CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) in female liver than in male liver. Mice were treated with xenobiotic activators of AhR, CAR, PXR, PPARα, or Nrf2 and their associated marker genes were highly induced in liver by these xenobiotic activators. Transcription factor target gene induction occurred with minimal induction of their associated transcription factors. CAR expression was induced by the AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), leading to increased basal expression of Cyp2b10 mRNA and enhanced induction of Cyp2b10 by TCPOBOP. Mrp2, 3, and 4 induction was augmented by cotreatment with TCDD and TCPOBOP compared with treatment with either compound alone. These studies illustrate CAR induction by TCDD in mice, indicating that AhR may transcriptionally regulate CAR and thus enhance induction of key metabolism and transporter genes by the CAR activator TCPOBOP. Collectively, these studies illustrate the fact that some xenobiotic inducers may elicit their response through mechanisms involving transcription factor regulation.
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Pregnane X receptor
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Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and liver X receptor (LXR) are intracellular sensors for foreign chemicals and/or endogenous compounds. Docking of a ligand into the ligand-binding domain (LBD) of a nuclear receptor induces conformational changes and switches the nuclear receptor into an active conformation. In this study, we examined whether assembly assays to exploit the ligand-dependent interaction of N- and C-terminal regions of the LBD could be used for detection of ligands for PXR, CAR and LXR. Rifampicin, CITCO and T1317 significantly enhanced interactions for human PXR, human CAR and human LXR, respectively. The effects of ligands on the interaction of LBDs in PXR and CAR reflected the species differences in ligand response of PXR and CAR. In conclusion, it appears that the present assay, which exploits the interaction between N- and C-terminal regions of LBDs, is applicable to identify ligands. Keywords: constitutive androstane receptor, ligand, liver X receptor, mammalian two-hybrid assay, nuclear receptor, pregnane X receptor
Pregnane X receptor
Constitutive androstane receptor
Pregnane
Androstane
Liver X receptor
Docking (animal)
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The metabolism and elimination of drugs is mainly mediated by various cytochrome P450 (CYP) enzymes, conjugative enzymes, transporters, and efflux proteins. Members of these gene families are up-regulated at transcriptional level by drug exposure, thus leading to induction of drug metabolism and elimination. There is compelling evidence that this induction is controlled by two drug-activated nuclear receptors, constitutive androstane receptor (CAR), and pregnane X receptor (PXR). This mini-review summarizes the current knowledge of CAR and PXR, their DNA and ligand binding preferences, expression patterns and polymorphisms, mechanisms of activation, and target genes. Keywords: nuclear receptors car, pxr, drugs elimination, cytochrome p450, efflux proteins, pregnane, target genes
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Efflux
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The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two closely related and liver-enriched nuclear hormone receptors originally defined as xenobiotic receptors. PXR and CAR regulate the transcription of drug-metabolizing enzymes and transporters, which are essential in protecting our bodies from the accumulation of harmful chemicals. An increasing body of evidence suggests that PXR and CAR also have an endobiotic function that impacts energy homeostasis through the regulation of glucose and lipids metabolism. Of note and in contrast, disruptions of energy homeostasis, such as those observed in obesity and diabetes, also have a major impact on drug metabolism. This review will focus on recent progress in our understanding of the integral role of PXR and CAR in drug metabolism and energy homeostasis.
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Constitutive androstane receptor
Energy homeostasis
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Constitutive androstane receptor
Pregnane X receptor
CYP3A
CYP1B1
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Artemisia annua tea is a popular dosage form used to treat and prevent malaria in some developing countries. However, repeated drinking leads to an obviously decreased efficacy, which may be related to the induction of metabolizing enzymes by artemisinin. In the present study, the ability of different components in A. annua to activate the pregnane X receptor and constitutive androstane receptor was evaluated by the dual luciferase reporter gene system. The changes in mRNA and protein expression of CYP3A4 and CYP2B6 were determined by quantitative real-time PCR and Western blotting. Results showed that in the pregnane X receptor-mediated CYP3A4 reporter gene system, chrysosplenetin and arteannuin B exhibited a weak induction effect on pregnane X receptor wt, while arteannuin A had a strong induction effect on pregnane X receptor wt and pregnane X receptor 370 and a weak induction effect on pregnane X receptor 163. In the pregnane X receptor-mediated CYP2B6 reporter gene system, arteannuin A had a moderate induction effect on pregnane X receptor wt and pregnane X receptor 379, and a weak induction effect on pregnane X receptor 403, while arteannuin B had a weak induction effect on pregnane X receptor wt and pregnane X receptor 379. Arteannuin A had a strong induction effect on constitutive androstane receptor 3 in constitutive androstane receptor-mediated CYP3A4/2B6 reporter gene systems, while arteannuin B showed a weak induction effect on constitutive androstane receptor 3 in the constitutive androstane receptor-mediated CYP2B6 reporter gene system. The mRNA and protein expressions of CYP3A4 and CYP2B6 were increased when the pregnane X receptor or constitutive androstane receptor was activated. Various components present in A. annua differentially affect the activities of pregnane X receptor isoforms and the constitutive androstane receptor, which indicates the possibility of a drug-drug interaction. This partly explains the decline in efficacy after repeated drinking of A. annua tea.
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Constitutive androstane receptor
Pregnane
CYP2B6
Androstane
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The metabolism and elimination of drugs is mainly mediated by cytochrome P450 (CYP) enzymes, aided by conjugative enzymes and transport proteins. An integral aspect of this elimination process is the induction of drug metabolism through activation of gene expression of metabolic and transport proteins. There is compelling evidence that induction is regulated by drug-activated nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR). This review outlines the basic properties of CAR and PXR, their ligands and target genes, and the mechanisms of the induction process. The implications of nuclear receptor-mediated induction for drug research are also discussed.
Pregnane X receptor
Constitutive androstane receptor
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