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

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.