Bernardini S, Hirvonen A, Järventaus H, Norppa H
Laboratory of Molecular and Cellular Toxicology, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 b, FIN-00250 Helsinki, Finland.
Mutagenesis. 2001 May;16(3):277-81. doi: 10.1093/mutage/16.3.277.
About 50% and 15% of Caucasians lack the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes and the corresponding enzyme activity, respectively. Both of these polymorphisms have been shown to affect the genotoxicity of some epoxides in cultured human lymphocytes. Especially GSTT1 appears to be important in whole-blood cultures, probably because GSTT1 activity is high in erythrocytes. The in vitro genotoxicity of trans-stilbene oxide (TSO), a model substrate for GSTM1, has been shown to depend on individual GSTM1 activity. The potential role of GSTM1 genotype, and the possible interference of GSTT1 genotype, has not previously been examined in this context. We have studied TSO-induced sister chromatid exchanges (SCEs) in 72 h whole-blood lymphocyte cultures from 24 healthy human donors, representing different combinations of GSTM1 and GSTT1 positive and null genotypes. TSO clearly increased SCEs in cultures of all donors. The mean number of SCEs per cell induced by 75 and 150 microM TSO was, respectively, 1.5- and 1.3-times higher in cultures of GSTM1 null than GSTM1 positive donors. In another experiment, GSTM1 null individuals showed, in comparison with GSTM1 positive subjects, a 1.8-fold SCE induction by 50 microM TSO. GSTT1 genotype did not have an unequivocal effect. Our findings suggest that the lack of the GSTM1 gene, resulting in reduced detoxification capacity, increases individual sensitivity to the genotoxic effects of TSO.
约50%的白种人缺乏谷胱甘肽S-转移酶M1（GSTM1）基因，15%的白种人缺乏谷胱甘肽S-转移酶T1（GSTT1）基因，且分别缺乏相应的酶活性。已表明这两种基因多态性均会影响培养的人淋巴细胞中某些环氧化物的遗传毒性。尤其是GSTT1在全血培养中似乎很重要，这可能是因为GSTT1在红细胞中的活性很高。反式氧化茋（TSO）是GSTM1的一种模型底物，其体外遗传毒性已表明取决于个体的GSTM1活性。此前尚未在此背景下研究GSTM1基因型的潜在作用以及GSTT1基因型可能产生的干扰。我们研究了来自24名健康人类供体的72小时全血淋巴细胞培养物中TSO诱导的姐妹染色单体交换（SCE）情况，这些供体代表了GSTM1和GSTT1阳性及缺失基因型的不同组合。TSO明显增加了所有供体培养物中的SCE。在GSTM1缺失的供体培养物中，75和150微摩尔TSO诱导的每细胞SCE平均数分别比GSTM1阳性供体培养物中的高1.5倍和1.3倍。在另一项实验中，与GSTM1阳性受试者相比，GSTM1缺失个体在50微摩尔TSO作用下的SCE诱导率高1.8倍。GSTT1基因型没有明确的影响。我们的研究结果表明，GSTM1基因的缺失导致解毒能力降低，增加了个体对TSO遗传毒性作用的敏感性。
