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

• DOI: 10.1158/1078-0432.ccr-08-0411
• Publication Date: 2008-11-03T08:27:42Z
• Authors: Edwin Sandanaraj; Suman Lal; Viknesvaran Selva...; London Lucien Ooi; Zee Wan Wong; Nan Soon Wong; Peter Cher Siang Ang; Edmund J.D. Lee; Balram Chowbay
• Keywords: Pregnane X receptor

Abstract Purpose: To characterize pregnane X receptor (PXR) polymorphic variants in healthy Asian populations [Chinese, Malay and Indian (n = 100 each)], to investigate the association between PXR haplotypes hepatic mRNA expression of its downstream target genes, CYP3A4 ABCB1, as well their influence on clearance doxorubicin breast cancer patients. Experimental Design: genotyping was done by direct DNA sequencing, haplotype clusters were derived expectation-maximization algorithm. Genotype-phenotype correlations using Mann-Whitney U test Kruskal-Wallis test. Results: Significant interethnic variations observed pharmacogenetics among three ethnic groups. The liver tissues harboring PXR*1B 4-fold lower compared with non-PXR*1B (*1A + *1C) [PXR*1B versus PXR*1A; P 0.015; PXR*1C; 0.023]. PXR*1B-bearing associated significantly (PXR*1B non-PXR*1B, 0.030) ABCB1 0.060) non–PXR*1B-bearing tissues. Doxorubicin patients carrying CL/BSA (L h−1 m−2): 20.84 (range, 8.68-29.24) 24.85 13.80-55.66), 0.022]. Conclusions: This study showed that reduced targets, ABCB1. correlates be clearance, suggesting constitution could important influencing interindividual disposition putative drug substrates.