Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects.
The pregnane X receptor (PXR) is the main transcriptional regulator of many enzymes that metabolize xenobiotics such as P450s and drug transporters. Polymorphisms in the PXR gene contribute to population variability in CYP3A4 and P-glycoprotein levels. Single nucleotide polymorphisms (SNPs) have been reported in Caucasian, African-American and Japanese populations. In the present study, we identified the known SNP, V140M and a novel SNP, Q158K, in Chinese subjects. We developed an allele-specific polymerase chain reaction method to detect the novel allele and found its frequency in 451 Chinese subjects to be 2.2%. CYP3A4-luciferase reporter assays revealed that the Q158K variant gave rise to much lower levels of CYP3A4 promoter activity in LS174T and HepG2 cells exposed to the PXR ligands, rifampin and paclitaxel, than did wild-type PXR. The SNP had less effect on promoter activity in response to clotrimazole or nifedipine.
Lim
Yun-Ping
YP
Institute of Basic Medical Sciences, Medical College, National Cheng Kung University, Tainan, Taiwan.
Liu
Chin-Hung
CH
Shyu
Lih-Jen
LJ
Huang
Jin-Ding
JD
D001483:Base Sequence; D045744:Cell Line, Tumor; D002681:China; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid