Norwegian Institute for Air Research, Kjeller, Norway.
Mutat Res. 2012 Aug 1;736(1-2):130-7. doi: 10.1016/j.mrfmmm.2012.03.003. Epub 2012 Mar 20.
Glutathione S-transferases (GSTs) are members of a multigene family of isoenzymes that are important in the control of oxidative stress and in phase II metabolism. Acting non-enzymically, GSTs can modulate signalling pathways of cell proliferation, cell differentiation and apoptosis. Using a molecular epidemiology approach, we have investigated a potential involvement of GSTs in DNA damage processing, specifically the modulation of DNA repair in a group of 388 healthy adult volunteers; 239 with at least 5 years of occupational exposure to asbestos, stone wool or glass fibre, and 149 reference subjects. We measured DNA damage in lymphocytes using the comet assay (alkaline single cell gel electrophoresis): strand breaks (SBs) and alkali-labile sites, oxidised pyrimidines with endonuclease III, and oxidised purines with formamidopyrimidine DNA glycosylase. We also measured GST activity in erythrocytes, and the capacity for base excision repair (BER) in a lymphocyte extract. Polymorphisms in genes encoding three GST isoenzymes were determined, namely deletion of GSTM1 and GSTT1 and single nucleotide polymorphism Ile105Val in GSTP1. Consumption of vegetables and wine correlated negatively with DNA damage and modulated BER. GST activity correlated with oxidised bases and with BER capacity, and differed depending on polymorphisms in GSTP1, GSTT1 and GSTM1. A significantly lower BER rate was associated with the homozygous GSTT1 deletion in all asbestos site subjects and in the corresponding reference group. Multifactorial analysis revealed effects of sex and exposure in GSTP1 Ile/Val heterozygotes but not in Ile/Ile homozygotes. These variants affected also SBs levels, mainly by interactions of GSTP1 genotype with exposure, with sex, and with smoking habit; and by an interaction between sex and smoking. Our results show that GST polymorphisms and GST activity can apparently influence DNA stability and repair of oxidised bases, suggesting a potential new role for these proteins in DNA damage processing via DNA damage signalling.
谷胱甘肽 S-转移酶（GSTs）是多基因家族同工酶的成员，在控制氧化应激和 II 期代谢中具有重要作用。非酶促作用下，GSTs 可调节细胞增殖、细胞分化和凋亡的信号通路。我们采用分子流行病学方法，研究 GSTs 是否参与 DNA 损伤处理，特别是在一组 388 名健康成年志愿者中调节 DNA 修复：239 名志愿者至少有 5 年职业性接触石棉、岩棉或玻璃纤维，149 名参考对象。我们使用彗星试验（碱性单细胞凝胶电泳）检测淋巴细胞中的 DNA 损伤：链断裂（SBs）和碱不稳定位点、内切酶 III 检测氧化嘧啶、内切酶 V 检测氧化嘌呤。我们还测量了红细胞中的 GST 活性和淋巴细胞提取物中的碱基切除修复（BER）能力。测定了编码三种 GST 同工酶的基因多态性，即 GSTM1 和 GSTT1 缺失和 GSTP1 中的 Ile105Val 单核苷酸多态性。蔬菜和葡萄酒的摄入与 DNA 损伤呈负相关，并调节 BER。GST 活性与氧化碱基和 BER 能力相关，且因 GSTP1、GSTT1 和 GSTM1 的多态性而不同。所有石棉场所的 GSTT1 纯合缺失和相应的参考组中，BER 率明显较低。多因素分析显示 GSTP1 Ile/Val 杂合子中的性别和暴露因素的影响，但在 Ile/Ile 纯合子中没有。这些变体还影响 SBs 水平，主要通过 GSTP1 基因型与暴露、性别和吸烟习惯的相互作用；以及性别和吸烟之间的相互作用。我们的结果表明，GST 多态性和 GST 活性显然可以影响 DNA 稳定性和氧化碱基的修复，表明这些蛋白在 DNA 损伤通过 DNA 损伤信号转导的处理中具有潜在的新作用。
