Dataset Information

The PXR is a drug target for chronic inflammatory liver disease.

ABSTRACT:

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PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A - which more effectively prevents PBC recurrence in transplanted patients than FK506 - is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract inflammatory cell recruitment), feeding a PXR activator inhibited inflammation, TNFalpha and Il-1alpha mRNA expression in SJL/J-PXR(+/+), but not SJL/J-PXR(-/-). Monocytic cells - a major source of inflammatory mediators such as TNFalpha - expressed the PXR and PXR activators inhibited endotoxin-induced NF-kappaB activation and TNFalpha expression. PXR activation also inhibited endotoxin-stimulated TNFalpha secretion from liver monocytes/macrophages isolated from PXR(+/+) mice, but not from cells isolated from PXR(-/-) mice. To confirm that PXR activation inhibits NF-kappaB in vivo, 3x-kappaB-luc fibrotic mice (which express a luciferase gene regulated by NF-kappaB) were imaged after treatment with the hepatotoxin CCl(4). PXR activator inhibited the induction of hepatic NF-kappaB activity without affecting CCl(4) toxicity/hepatic damage. Using a PXR reporter gene assay, cyclosporin A - but not FK506 - was shown to be a direct PXR activator, and also to induce expression of the classic PXR-regulated CYP3A4 gene in human hepatocytes and in a cell line null for the FXR, a nuclear receptor with similar properties to the PXR.

Conclusion

PXR activation is anti-inflammatory in the liver and the effects of cyclosporin A in PBC disease recurrence may be mediated in part via the PXR. Since PXR activation promotes hepatocyte growth and is also anti-fibrogenic, the PXR may be an excellent drug target for the treatment of chronic inflammatory liver disease.

SUBMITTER: Wallace K

PROVIDER: S-EPMC2937210 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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The PXR is a drug target for chronic inflammatory liver disease.

Wallace Karen K Cowie David E DE Konstantinou Dimitrios K DK Hill Stephen J SJ Tjelle Torunn E TE Axon Andrew A Koruth Matthew M White Steven A SA Carlsen Harald H Mann Derek A DA Wright Matthew C MC

The Journal of steroid biochemistry and molecular biology 20100421 2-3

<h4>Unlabelled</h4>PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A - which more effectively prevents PBC recurrence in transplanted patients than FK506 - is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract i ...[more]

PMID: 20416375

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Project description:The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in the liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200mg/kg, i.p. once daily for 4days in corn oil) or the prototypical CAR ligand TCPOBOP (3mg/kg, i.p., once daily for 4days in corn oil). At the given doses, TCPOBOP differentially regulated many more genes (2125) than PCN (212), and 147 of the same genes were differentially regulated by both chemicals. As expected, the top pathways differentially regulated by both PCN and TCPOBOP were involved in xenobiotic metabolism, and they also up-regulated genes involved in retinoid metabolism, but down-regulated genes involved in inflammation and iron homeostasis. Regarding unique pathways, PXR activation appeared to overlap with the aryl hydrocarbon receptor signaling, whereas CAR activation appeared to overlap with the farnesoid X receptor signaling, acute-phase response, and mitochondrial dysfunction. The mRNAs of differentially regulated drug-processing genes (DPGs) partitioned into three patterns, namely TCPOBOP-induced, PCN-induced, as well as TCPOBOP-suppressed gene clusters. The cumulative mRNAs of the differentially regulated DPGs, phase-I and -II enzymes, as well as efflux transporters were all up-regulated by both PCN and TCPOBOPOP, whereas the cumulative mRNAs of the uptake transporters were down-regulated only by TCPOBOP. The absolute mRNA abundance in control and receptor-activated conditions was examined in each DPG category to predict the contribution of specific DPG genes in the PXR/CAR-mediated pharmacokinetic responses. The preferable differential regulation by TCPOBOP in the entire hepatic transcriptome correlated with a marked change in the expression of many DNA and histone epigenetic modifiers. In conclusion, the present study has revealed known and novel, as well as common and unique targets of PXR and CAR in mouse liver following pharmacological activation using their prototypical ligands. Results from this study will further support the role of these receptors in regulating the homeostasis of xenobiotic and intermediary metabolism in the liver, and aid in distinguishing between PXR and CAR signaling at various physiological and pathophysiological conditions. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Project description:BACKGROUND:Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-?B not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-?B1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-?B1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI). MATERIALS AND METHODS:A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-?B1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. RESULTS:The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42-0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-?B1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06-3.43, p = 0.028 and OR 1.81; 1.06-3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs. CONCLUSION:Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-?B1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.

Dataset Information

The PXR is a drug target for chronic inflammatory liver disease.

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Conclusion

Publications

The PXR is a drug target for chronic inflammatory liver disease.

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