Moyer Ann M, Salavaggione Oreste E, Wu Tse-Yu, Moon Irene, Eckloff Bruce W, Hildebrandt Michelle A T, Schaid Daniel J, Wieben Eric D, Weinshilboum Richard M
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School-Mayo Clinic, Rochester, Minnesota, USA.
Cancer Res. 2008 Jun 15;68(12):4791-801. doi: 10.1158/0008-5472.CAN-07-6724.
Glutathione S-transferase P1 (GSTP1) is of importance for cancer research because of its role in detoxifying carcinogens, activating antineoplastic prodrugs, metabolizing chemotherapeutic agents, and its involvement in cell cycle and apoptosis regulation. Two common GSTP1 genetic polymorphisms have been studied extensively. However, the full range of GSTP1 genetic variation has not been systematically characterized in the absence of disease pathology. We set out to identify common GSTP1 polymorphisms in four ethnic groups, followed by functional genomic studies. All exons, splice junctions, and the 5'-flanking region of GSTP1 were resequenced using 60 DNA samples each from four ethnic groups. The 35 single-nucleotide polymorphisms (SNP) identified included six nonsynonymous SNPs and 17 previously unreported polymorphisms. GSTP1 variant allozymes were then expressed in COS-1 cells, and five displayed significantly altered levels of enzyme activity. One decreased to 22% of the wild-type (WT) activity. Four variant allozymes had K(m) values that differed significantly from that of the WT, and five showed altered levels of immunoreactive protein compared with WT, with a significant correlation (r = 0.79, P < 0.007) between levels of immunoreactive protein and enzyme activity in these samples. In the Mexican American population, five linked SNPs were significantly associated with GSTP1 mRNA expression, one of which was found by electrophoretic mobility shift assay to alter protein binding. These studies have identified functionally significant genetic variation, in addition to the two frequently studied GSTP1 nonsynonymous SNPs, that may influence GSTP1's contribution to carcinogen and drug metabolism, and possibly disease pathogenesis and/or drug response.
谷胱甘肽S-转移酶P1（GSTP1）在癌症研究中具有重要意义，因为它在致癌物解毒、抗肿瘤前体药物激活、化疗药物代谢以及细胞周期和细胞凋亡调节中发挥作用。两种常见的GSTP1基因多态性已得到广泛研究。然而，在没有疾病病理的情况下，GSTP1基因变异的全貌尚未得到系统表征。我们着手在四个种族群体中鉴定常见的GSTP1多态性，随后进行功能基因组学研究。使用来自四个种族群体的各60个DNA样本对GSTP1的所有外显子、剪接位点和5'侧翼区域进行重测序。鉴定出的35个单核苷酸多态性（SNP）包括6个非同义SNP和17个先前未报道的多态性。然后在COS-1细胞中表达GSTP1变异同工酶，其中5种显示酶活性水平有显著改变。一种降至野生型（WT）活性的22%。四种变异同工酶的K（m）值与WT有显著差异，与WT相比，5种显示免疫反应性蛋白水平改变，这些样本中免疫反应性蛋白水平与酶活性之间存在显著相关性（r = 0.79，P < 0.007）。在墨西哥裔美国人群体中，5个连锁SNP与GSTP1 mRNA表达显著相关，其中一个通过电泳迁移率变动分析发现可改变蛋白质结合。这些研究除了鉴定出两个经常研究的GSTP1非同义SNP外，还发现了功能上具有重要意义的基因变异，这些变异可能影响GSTP1在致癌物和药物代谢中的作用，以及可能影响疾病发病机制和/或药物反应。
