The effects of splicing variant of PXR PAR-2 on CYP3A4 and MDR1 mRNA expressions

Background: PAR-2(SV1), a splicing variant of PXR, has similar activity as PXR wild type. Currently, a 6bp-deletion variant ((-133)GAGAAG(-128)) in promoter region of PAR-2(SV1) was reported, which could diminish the hPAR-2 promote activity in HepG2 cells. The distribution and functions of 6bp-deletion in Chinese were investigated. Methods: The PXR genotype was analyzed from 56 liver samples and 177 blood samples. Then the mRNA expression of PAR-2(SV1), total PXR, CYP3A4 and MDR1 were quantitatively analyzed by real-time PCR. Results: The allelic frequencies of 6bp-deletion were 22.4%, 38.4% and 23.7%, in blood of Chinese healthy (n = 177), hepatic carcinoma samples (n = 33) and calculus of bile duct ones (n = 23) respectively. PAR-2 (SV1) transcript represented approximately 15.3% of the total PXR transcripts in all liver samples. The 6bp-deletion cut down PAR-2(SV1) mRNA and total PXR mRNA transcriptional expression, and then led to down regulations of MDR1 and CYP3A4. Conclusions: PAR-2(SV1) plays an important role in total PXR mRNA expression. The 6bp-deletion affects the PAR-2(SV1) expression greatly, and then contributes to the adjustment of expression and function of total PXR. Thus it leads to the changed target gene expressions. which may partly explain interindividual variations in CYP3A4 and MDR1. And these phenomena suggest that individuals with 6bp-deletion are prone to carcinoma when exposed to toxicity. (C) 2009 Elsevier B.V. All rights reserved.