Uusküla M, Järventaus H, Hirvonen A, Sorsa M, Norppa H
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
Carcinogenesis. 1995 Apr;16(4):947-50. doi: 10.1093/carcin/16.4.947.
Glutathione S-transferase M1 (GSTM1), catalyzing the conjugation of various reactive molecules with glutathione (GSH), shows genetic polymorphism in humans. Almost half of all Caucasians lack the GSTM1 gene, being theoretically at a higher risk from the toxic effects of substrates for GSTM1. The purpose of the present study was to investigate whether the GSTM1 genotype of lymphocyte donors influences the in vitro induction of sister chromatid exchanges (SCEs) by styrene-7,8-oxide (SO) and 1,2-epoxy-3-butene (MEB), the epoxide metabolites of styrene and butadiene respectively and potential substrates for GSTM1. SCEs induced after a 48 h treatment (started 24 h after culture initiation) by two different concentrations of SO (50 and 150 microM) and MEB (50 and 250 microM) were analyzed in cultured (72 h) lymphocytes of six GSTM1 null (gene deleted) and six GSTM1-positive (gene present) donors. Both SO and MEB were found to clearly increase SCEs. The GSTM1 genotype had no influence on SCE induction by SO. In contrast, MEB produced a higher level of SCEs among the GSTM1 null than GSTM1-positive samples. At 250 microM MEB, the GSTM1 null donors showed 31% more induced SCEs (on average seven more SCEs per cell) than the GSTM1-positive donors (P = 0.02, acetone treatment as the reference). Furthermore, the GSTM1 null genotype was associated with a slight decrease in mitotic index and replication index, regardless of the treatment. The results suggest that GSTM1-mediated GSH conjugation is an important detoxification pathway for MEB, but not for SO, in cultured human lymphocytes.
谷胱甘肽S-转移酶M1（GSTM1）催化各种活性分子与谷胱甘肽（GSH）结合，在人类中表现出基因多态性。几乎一半的白种人缺乏GSTM1基因，理论上因GSTM1底物的毒性作用而面临更高风险。本研究的目的是调查淋巴细胞供体的GSTM1基因型是否会影响苯乙烯-7,8-氧化物（SO）和1,2-环氧-3-丁烯（MEB）对姐妹染色单体交换（SCE）的体外诱导作用，SO和MEB分别是苯乙烯和丁二烯的环氧化代谢产物，也是GSTM1的潜在底物。在六个GSTM1基因缺失（基因删除）和六个GSTM1阳性（基因存在）供体的培养（72小时）淋巴细胞中，分析了两种不同浓度的SO（50和150微摩尔）和MEB（50和250微摩尔）在48小时处理（培养开始24小时后开始）后诱导的SCE。发现SO和MEB均能明显增加SCE。GSTM1基因型对SO诱导SCE没有影响。相反，MEB在GSTM1基因缺失样本中诱导的SCE水平高于GSTM1阳性样本。在250微摩尔MEB处理下，GSTM1基因缺失供体诱导的SCE比GSTM1阳性供体多31%（平均每个细胞多七个SCE）（P = 0.02，以丙酮处理作为对照）。此外，无论处理如何，GSTM1基因缺失基因型与有丝分裂指数和复制指数的轻微降低有关。结果表明，在培养的人淋巴细胞中，GSTM1介导的GSH结合是MEB的重要解毒途径，但不是SO的解毒途径。
