title: The effects of splicing variant of PXR PAR-2 on CYP3A4 and MDR1 mRNA expressions.
abstract: 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.
authors.affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Ji
authors.forename: You
authors.initials: Y
authors.lastname: Yin
authors.forename: Lan
authors.initials: L
authors.lastname: Fan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Huang
authors.initials: H
authors.lastname: Yun
authors.forename: Nianci
authors.initials: N
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Zhang
authors.initials: Z
authors.lastname: Wei
authors.forename: Dongshen
authors.initials: D
authors.lastname: Ouyang
authors.forename: Hong-Hao
authors.initials: HH
authors.lastname: Zhou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human