PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

Hor, S Y; Lee, S C; Wong, Chin‐Ho; Lim, Yi Wan; Lim, Robert C.; Wang, L Z; Fan, Li; Guo, Jia; Lee, H S; Goh, Boon Cher; Tan, Thiam Soon

doi:10.1038/sj.tpj.6500478

Cited by 57 publications

(40 citation statements)

References 35 publications

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“…The results of the present study differ from a recent study by Hor et al (28) in which the investigators failed to show a relationship between PXR, CAR, HNF4a, or CYP3A5*3 polymorphisms and the pharmacokinetics of doxorubicin or docetaxel in Asian breast cancer patients. The reason for the discrepancy between their results and the present study is unclear.…”

Section: Discussioncontrasting

confidence: 57%

PXR Pharmacogenetics: Association of Haplotypes with Hepatic CYP3A4 and ABCB1 Messenger RNA Expression and Doxorubicin Clearance in Asian Breast Cancer Patients

Sandanaraj

Lal

Selvarajan

et al. 2008

Clinical Cancer Research

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Purpose: To characterize pregnane X receptor (PXR) polymorphic variants in healthy Asian populations [Chinese, Malay and Indian (n = 100 each)], and to investigate the association between PXR haplotypes and hepatic mRNA expression of PXR and its downstream target genes, CYP3A4 and ABCB1, as well as their influence on the clearance of doxorubicin in Asian breast cancer patients. Experimental Design: PXR genotyping was done by direct DNA sequencing, and PXR haplotypes and haplotype clusters were derived by expectation-maximization algorithm. Genotype-phenotype correlations were done using Mann-Whitney U test and Kruskal-Wallis test. Results: Significant interethnic variations were observed in PXR pharmacogenetics among the threeAsian ethnic groups.The expression of PXR mRNA in liver tissues harboring the PXR*1B haplotype clusters was 4-fold lower compared with the non-PXR*1B (*1A + *1C) haplotype clusters [PXR*1B versus PXR*1A ; P = 0.015; PXR*1B versus PXR*1C ; P = 0.023]. PXR*1B-bearing liver tissues were associated with significantly lower expression of CYP3A4 (PXR*1B versus non-PXR*1B, P = 0.030) and ABCB1 (PXR*1B versus non-PXR*1B, P = 0.060) compared with non^PXR*1B-bearing liver tissues. Doxorubicin clearance in breast cancer patients harboring the PXR*1B haplotypes was significantly lower compared with patients carrying the non-PXR*1B haplotypes [PXR*1B versus non-PXR*1B, CL/BSA (L h Conclusions: This study showed that PXR*1B was associated with reduced hepatic mRNA expression of PXR and its downstream targets, CYP3A4 and ABCB1. Genotype-phenotype correlates in breast cancer patients showed PXR*1B to be significantly associated with lower doxorubicin clearance, suggesting that PXR haplotype constitution could be important in influencing interindividual and interethnic variations in disposition of its putative drug substrates.

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Section: Discussioncontrasting

confidence: 57%

PXR Pharmacogenetics: Association of Haplotypes with Hepatic CYP3A4 and ABCB1 Messenger RNA Expression and Doxorubicin Clearance in Asian Breast Cancer Patients

Sandanaraj

Lal

Selvarajan

et al. 2008

Clinical Cancer Research

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“…127 It was already described that genetic variants such as splicing isoforms of PXR and CAR can affect the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients. 106 A recent study also showed that the NOVA2 gene interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. 106 The authors emphasize that genetic polymorphisms are important factors for modulation of the drug effect, illustrating alternative splicing as a potential therapeutic target and the importance of considering the activity of compounds at alternative splice isoforms in screening programs.…”

Section: Alternative Splicing In Drug Resistance Activation and Metamentioning

confidence: 99%

“…106 A recent study also showed that the NOVA2 gene interacts with a cis-acting polymorphism to influence the proportions of drug-responsive splice variants of SCN1A. 106 The authors emphasize that genetic polymorphisms are important factors for modulation of the drug effect, illustrating alternative splicing as a potential therapeutic target and the importance of considering the activity of compounds at alternative splice isoforms in screening programs. 128 In that regard, variations in the production of an HMGCR splice isoform were connected to reduced statin sensitivity and associated with interindividual differences in the metabolism of this drug.…”

Section: Alternative Splicing In Drug Resistance Activation and Metamentioning

confidence: 99%

The impact of microRNAs and alternative splicing in pharmacogenomics

2009

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“…Several studies have described genetic variations in the PXR gene, including other NRs, encoding for transporters and DMEs, and some of these have been associated with the pharmacological effects of several drugs [85][86][87][88] , which is due to functional changes in NR expression. Therefore, it is likely that inter-individual variability in the clinical responses to several drugs will be understood through PXR genetic polymorphisms [89] .…”

Section: Pxr Pharmacogenetic Effectsmentioning

confidence: 99%

“…A study of 101 patients with breast cancer from three Asian ethnic groups showed genotypic variations in the PXR transcriptional regulator rs1523127 (A>C). CAR and HNF4α have not been associated with docetaxel or doxorubicin pharmacokinetics or pharmacodynamics [86] . However, PXR rs2276707 in combination with rs3814058 (T>C) in the 3′ untranslated region (UTR) lowered doxorubicin clearance in 311 patients with breast cancer undergoing adjuvant treatment with doxorubicin and cyclophosphamide [94] .…”

Section: Pxr Pharmacogenetic Effectsmentioning

confidence: 99%

Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

2015

Receptors Clin Investig

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The pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of phase I and phase II drug metabolizing enzymes and transporters involved in the absorption, distribution, metabolism, and elimination of xenobiotics. PXR is expressed predominantly in the liver and intestine and resembles cytochrome P450s (CYPs), which is a phase I drug metabolizing enzyme. It is estimated that CYP 3As and CYP2Cs metabolize > 50% of all prescription drugs. PXR upregulates gene expression of these CYPs. Therefore, PXR plays a crucial role detoxifying xenobiotics and could potentially have effects on drug-drug interactions. PXR is reportedly responsible for activating a variety of target genes through cross-talk with other nuclear receptors and coactivators at transcriptional and translation levels. Recent findings have demonstrated the regulatory role of PXR and show the potential use of a PXR antagonist during drug therapy. In addition, genetic variations in the PXR gene are associated with the pharmacological effects of several drugs, and inter-individual differences in the clinical response are likely to be understood through these PXR polymorphisms. Many approaches have been used to explain the PXR regulatory mechanisms, such as microRNA-mediated PXR post-translational regulation and diverse PXR haplotype analysis. Understanding these PXR polymorphisms may lead to improving personalized therapeutic treatments.Keywords: pregnane X receptor; drug metabolizing enzyme; polymorphism; personalized therapeutic treatment To cite this article: Jung Yeon Moon, et al. Role of the nuclear pregnane X receptor in drug metabolism and the clinical response. Receptor Clin Invest 2015; 2: e996.

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PXR, CAR and HNF4α genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients

Cited by 57 publications

References 35 publications

PXR Pharmacogenetics: Association of Haplotypes with Hepatic CYP3A4 and ABCB1 Messenger RNA Expression and Doxorubicin Clearance in Asian Breast Cancer Patients

PXR Pharmacogenetics: Association of Haplotypes with Hepatic CYP3A4 and ABCB1 Messenger RNA Expression and Doxorubicin Clearance in Asian Breast Cancer Patients

The impact of microRNAs and alternative splicing in pharmacogenomics

Role of the nuclear pregnane X receptor in drug metabolism and the clinical response

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