PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messenger RNA expression and doxorubicin clearance in Asian breast cancer patients.

Abstract

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 three Asian 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(-1) m(-2)): 20.84 (range, 8.68-29.24) versus 24.85 (range, 13.80-55.66), P=0.022].

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.

• Authors: Edwin Sandanaraj, Suman Lal, Viknesvaran Selvarajan, London Lucien Ooi, Zee Wan Wong, Nan Soon Wong, Peter Cher Siang Ang, Edmund J D Lee, Balram Chowbay
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 21 Pg. 7116-26 (Nov 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18981011 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Pregnane X Receptor
• RNA, Messenger
• Receptors, Steroid
• Doxorubicin
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Asian People (genetics)
• Breast Neoplasms (drug therapy, genetics, metabolism)
• Cytochrome P-450 CYP3A (metabolism)
• Doxorubicin (metabolism, therapeutic use)
• Female
• Gene Frequency
• Haplotypes
• Humans
• Linkage Disequilibrium
• Liver (metabolism)
• Polymorphism, Genetic
• Pregnane X Receptor
• RNA, Messenger (metabolism)
• Receptors, Steroid (genetics, metabolism)