Interplay of Pregnane X receptor with Other Nuclear Receptors on Gene Regulation

doi:10.2133/dmpk.23.14

Drug Metabolism and Pharmacokinetics

Volume 23, Issue 1, 2008, Pages 14-21

https://doi.org/10.2133/dmpk.23.14 Get rights and content

Summary:

Human body needs to protect itself from a diverse array of harmful chemicals. These chemicals are also involved in drug metabolism, enzyme induction, and can cause adverse drug-drug interactions. Being a member of nuclear receptors (NRs), pregnane X receptor (PXR) has recently emerged as transcriptional regulators of cytochrome P450 (CYP) and transporters expression so as to against xenobiotics exposure. This review describes some common nuclear receptors, i.e. farnesoid X receptor (FXR), small heterodimer partner (SHP), hepatocyte nuclear factor-4α (HNF-4α), liver X receptor (LXR), glucocorticoid receptor (GR), constitutive androstane receptor (CAR) that crosstalk with PXR and involvement of coregulators thus control target genes expression.

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The effects of LXR agonist T0901317 and LXR antagonist GSK2033 on morphogenesis and lipid properties in full thickness skin models
2020, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
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This might be explained by the fact that SCD-1 has a response element for both SREBP1 and LXR [16]. Besides the complexity of the in vitro and in vivo correlations, in literature it has been reported that T091317 and GSK2033 can activate other nuclear receptors, such as the pregane-X-receptor (PXR), farnesoid-X-receptor (FXR), vitamin D receptor (VDR) [43,51–54]. However, recently it was reported that specific VDR targeting by supplementation of 1,25(OH)2D3 did not lead to changes in the lipid composition of FTMs [55].
Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.
Activation of the aryl hydrocarbon receptor decreases rifampicin-induced CYP3A4 expression in primary human hepatocytes and HepaRG
2017, Toxicology Letters
The role of the cross-talk between nuclear receptors in the regulation of Cytochrome P450 expression in the liver is well-documented. Most studies have focused on the cross-talk between the pregnane X receptor (PXR) and other receptors, such as the constitutive androstane receptor. However, cross-talk between PXRs and aryl hydrocarbon receptors (AhRs) has also been suggested, but reports regarding this cross-talk are conflicting. In the present study, we treated HepaRG and primary human hepatocytes (PHHs) with both a strong (TCDD) and weak (3-methylindole; 3MI) AhR activator to investigate their impact on PXR-regulated expression of CYP3A4. Moreover, we investigated the effect of co-activation of PXR, using rifampicin, and AhR, using TCDD and 3MI, on the regulation of CYP3A4 induction. We also investigated whether knockdown of AhR using siRNA affected the basal expression of PXR and CYP3A4 and induction of CYP3A4 by rifampicin, TCDD and 3MI. The results showed that the treatment of HepaRG cells, but not of PHHs, with AhR activators decreased mRNA expression of CYP3A4 and PXR. Moreover, in both HepaRG and PHHs, AhR activation decreased rifampicin-induced expression of CYP3A4 mRNA. Knock-down of AhR in PHHs increased both basal and rifampicin-induced expression of CYP3A4 mRNA. In conclusion, the presented results suggested that the cross-talk between PXR and AhR plays a role in the regulation of CYP3A4 gene expression.
Warfarin, a potential pollutant in aquatic environment acting through Pxr signaling pathway and γ-glutamyl carboxylation of vitamin K-dependent proteins
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However longer exposures or higher environmental concentrations could trigger bleeding and/or skeletal disorders. Although this remains to be elucidated, the capacity of Pxr to form heterodimers with other nuclear receptors (Lim and Huang, 2008) could lead warfarin treatment to have side-effects on other organs/systems. Finally, zebrafish appears to be a suitable and promising model to screen for new and environmental-friendly oral anticoagulant agents for treatment of human thromboembolic and bleeding disorders as well as their potential effects on aquatic environments.
Warfarin-induced vitamin K (VK) recycling impairment is used worldwide as a rodenticide and human thromboembolic prophylactic. Since VK metabolism/signaling pathways have been conserved throughout vertebrate evolution, its release to the environment might impact on aquatic organisms. Present study assessed the toxic effect of warfarin (0, 5, 25 and 125 mg L⁻¹) on zebrafish development and characterized underlying mechanisms of action through qPCR analysis of VK-related genes. Expression of pregnane X receptor (pxr), the nuclear receptor binding vitamin K, was ubiquitous in zebrafish and suggests that warfarin exposure may interfere with several biological processes. Indeed, warfarin exposure of zebrafish larvae caused hemorrhages in brain, skeletal deformities and triggered ectopic calcifications, which may be the consequence of an altered γ-carboxylation of VK-dependent proteins and/or pxr signaling. This study provides new insights into warfarin effects as a bone homeostasis disruptor and soft tissue calcification inductor, and its potential risk for aquatic environments.
Expression of microRNAs, CYP1A1 and CYP2B1 in the livers and ovaries of female rats treated with DDT and PAHs
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Citation Excerpt :
These compounds are ligands for specific receptors such as AhR, CAR and PXR. The activated receptors translocate to the nucleus, dimerize with nuclear partners and bind to specific sequences in distal promoters, triggering the transcription of target genes (Handschin and Meyer, 2003; Lim and Huang, 2008; Graham and Lake, 2008). As a result, the mRNA level is increased and CYP protein synthesis increases.
In this study, we determined the expression level of miRNAs and the induction of CYP1A1 and CYP2B1 in the livers and ovaries of female Wistar rats treated with DDT, benzo[a]pyrene (BP), and 3-methylcholanthrene (MC). This study compared CYP1A/2B induction and miRNA expression levels to cast light on a possible role of miRNA in the tissue-specific induction of CYPs.
The induction of CYP1A1/2B1 enzymes was detected by ethoxy-, pentoxyresorufin O-dealkylation and Western blot analysis. The CYP1A1/2B1 gene expression was determined by RT—real time PCR. Relative levels of expression for selected in silico miR species were determined by real time PCR with small nuclear U₆ RNA employed as a reference gene.
After bioinformatic analysis, miR-21, 221, 222, and 429 were chosen as potential post-transcriptional regulators of rat CYP1A and CYP2B. It was shown that miR-21, 221, 222, and 429 expression levels decreased in the liver of DDT-, BP-, and MC-treated rats, whereas increases were observed in CYP1A1 and CYP2B1 mRNA expression levels and protein content, and EROD and PROD activities. Conversely, a tendency for elevated levels of miRNAs in the ovaries of inducer-treated female rats was observed. In the ovaries, a high level of CYP1A1 and CYP2B1 mRNA expression was observed, although protein content and enzyme activity were not visible.
These data suggest a potential involvement of miRNA in the post-transcriptional regulation of CYP1A and CYP2B in the livers and ovaries of chemically induced rats.
Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation
2014, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Citation Excerpt :
Therefore, a cross-talk exists between PXR and LXR that might be of relevance for the control of lipid metabolism in the skin. PXR interacts with two other NHR which are known to influence skin homeostasis [128,129], namely VDR [130] and AHR [131]. The effect of PXR activation in keratinocytes has not yet been investigated.
Epidermal lipid synthesis and metabolism are regulated by nuclear hormone receptors (NHR) and in turn epidermal lipid metabolites can serve as ligands to NHR. NHR form a large superfamily of receptors modulating gene transcription through DNA binding. A subgroup of these receptors is ligand-activated and heterodimerizes with the retinoid X receptor including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR) and pregnane X receptor (PXR). Several isotypes of these receptors exist, all of which are expressed in skin. In keratinocytes, ligand activation of PPARs and LXRs stimulates differentiation, induces lipid accumulation, and accelerates epidermal barrier regeneration. In the cutaneous immune system, ligand activation of all three receptors, PPAR, LXR, and PXR, has inhibitory properties, partially mediated by downregulation of the NF-kappaB pathway. PXR also has antifibrotic effects in the skin correlating with TGF-beta inhibition. In summary, ligands of PPAR, LXR and PXR exert beneficial therapeutic effects in skin disease and represent promising targets for future therapeutic approaches in dermatology. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

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ReviewInterplay of Pregnane X receptor with Other Nuclear Receptors on Gene Regulation

Summary:

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene

Arch. Biochem. Biophys.

Biochim. Biophys. Acta.

Gastroenterology

J. Biol. Chem.

J. Lipid Res.

J. Mol. Biol.

Hepatology

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J. Biol. Chem.

J. Lipid Res.

Biochem. Pharmacol.

FEBS. Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Drug Metab. Pharmacokinet.

Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction

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

SXR, a novel steroid and xenobiotic-sensing nuclear receptor

Genes Dev.

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions

J. Clin. Invest.

The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution

Mol. Endocrinol.

The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux

Nat. Med.

Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes. Sequential role of glucocorticoid receptor and pregnane X receptor

Eur. J. Biochem.

High volume bioassays to assess CYP3A4-mediated drug interactions: induction and inhibition in a single cell line

Drug Metab. Dispos.

Coordinate induction of both cytochrome P4503A and MDR1 by St. John's wort in healthy subjects

Clin. Pharmacol. Ther.

St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor

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

In vitro and in vivo drug interactions involving human CYP3A1

Annu. Rev. Pharmacol. Toxicol.

Trabectedin (Yondelis, formerly ET-743), a mass balance study in patients with advanced cancer

Invest. New Drugs

Nuclear receptor, pregnane X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile

Drug Metab. Dispos.

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

Mol. Pharmacol.

Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia

J. Clin. Invest.

Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)

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

Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response

Pharmacogenomics J.

Regulation of drug transporter gene expression by nuclear receptors

Drug Metab. Dispos.

Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor

Nature

A transcriptional co-repressor that interacts with nuclear hormone receptors

Nature

Unique forms of human and mouse nuclear receptor corepressor SMRT

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

SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor

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

Cross talk between xenobiotic detoxication and other signalling pathways: clinical and toxicological consequences

Xenobiotica

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

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

Review
Interplay of Pregnane X receptor with Other Nuclear Receptors on Gene Regulation