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

被引：18
作者：
Liu, Yan [1 ]
Ji, Wei [1 ,3 ]
Yin, You [2 ]
Fan, Lan [1 ]
Zhang, Jian [3 ]
Yun, Huang [4 ]
Wang, Nianci [1 ]
Li, Qing [1 ]
Wei, Zhang [1 ]
Ouyang, Dongshen [1 ]
Zhou, Hong-Hao [1 ]
机构：
[1] Cent S Univ, Inst Clin Pharmacol, Pharmacogenet Res Inst, Changsha 410078, Hunan, Peoples R China
[2] Second Mil Med Univ, Changzheng Hosp, Dept Neurol, Shanghai 200003, Peoples R China
[3] Shanghai Jiao Tong Univ, Dept Pharm, Xinhua Hosp, Sch Med, Shanghai 200092, Peoples R China
[4] Cent S Univ, Dept Gen Surg, Changsha 410078, Hunan, Peoples R China
来源：
CLINICA CHIMICA ACTA | 2009年 / 403卷 / 1-2期
基金：
芬兰科学院; 中国国家自然科学基金;
关键词：
PXR; PAR-2(SV1); Alternative splicing; 6bp-deletion; CYP3A4; MDR1; X-RECEPTOR PXR; IDENTIFICATION; NR1I2; SITE;
D O I：
10.1016/j.cca.2009.02.006
中图分类号：
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号：
1001 ;
摘要：
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.
引用
收藏
页码：142 / 144
页数：3
相关论文
共 14 条
  • [1] BENJAMIN JB, 2006, CELL 0714, P126
  • [2] Structure and function of the human nuclear xenobiotic receptor PXR
    Carnahan, VE
    Redinbo, MR
    [J]. CURRENT DRUG METABOLISM, 2005, 6 (04) : 357 - 367
  • [3] Identification of the novel splicing variants for the hPXR in human livers
    Fukuen, S
    Fukuda, T
    Matsuda, H
    Sumida, A
    Yamamoto, I
    Inaba, T
    Azuma, J
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 298 (03) : 433 - 438
  • [4] JATINDER L, 2004, CURR DRUG METAB, V6, P369
  • [5] Functional characterization of four naturally occurring variants of human pregnane X receptor (PXR): One variant causes dramatic loss of both DNA binding activity and the transactivation of the CYP3A4 promoter/enhancer region
    Koyano, S
    Kurose, K
    Saito, Y
    Ozawa, S
    Hasegawa, R
    Komamura, K
    Ueno, K
    Kamakura, S
    Kitakaze, M
    Nakajima, T
    Matsumoto, K
    Akasawa, A
    Saito, H
    Sawada, JI
    [J]. DRUG METABOLISM AND DISPOSITION, 2004, 32 (01) : 149 - 154
  • [6] 5′ Diversity of human hepatic PXR (NR1I2) transcripts and identification of the major transcription initiation site
    Kurose, K
    Koyano, S
    Ikeda, S
    Tohkin, M
    Hasegawa, R
    Sawada, JI
    [J]. MOLECULAR AND CELLULAR BIOCHEMISTRY, 2005, 273 (1-2) : 79 - 85
  • [7] PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators
    Lamba, V
    Yasuda, K
    Lamba, JK
    Assem, M
    Davila, J
    Strom, S
    Schuetz, EG
    [J]. TOXICOLOGY AND APPLIED PHARMACOLOGY, 2004, 199 (03) : 251 - 265
  • [8] Owen A, 2004, ANTIVIR THER, V9, P819
  • [9] Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)
    Sonoda, J
    Xie, W
    Rosenfeld, JM
    Barwick, JL
    Guzelian, PS
    Evans, RM
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (21) : 13801 - 13806
  • [10] Phenobarbital response elements of cytochrome P450 genes and nuclear receptors
    Sueyoshi, T
    Negishi, M
    [J]. ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2001, 41 : 123 - 143
12