Bernardini S, Hirvonen A, Pelin K, Norppa H
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
Carcinogenesis. 1998 Feb;19(2):377-80. doi: 10.1093/carcin/19.2.377.
The influence of glutathione S-transferase T1 (GSTT1) genotype on the genotoxicity of 1,2-epoxy-3-butene (MEB), a metabolite of 1,3-butadiene, was assessed by the analysis of sister chromatid exchanges (SCEs) in 72-h human whole-blood lymphocyte cultures. The cultures were from 18 donors, representing both GSTT1 'positive' genotype (with at least one undeleted GSTT1 allele; GSTT1 activity present) and GSTT1 'null' genotype (homozygous deletion of the GSTT1 gene; no GSTT1 activity). As we have previously observed that allelism of glutathione S-transferase M1 (GSTM1) affects SCE induction by MEB in cultured lymphocytes, only individuals with the GSTM1 null genotype were included in this study. At 125 and 250 microM MEB (treatment at 24 h for 48 h), the mean frequencies of MEB-induced SCEs per cell (control level subtracted) were 4.5 (SD 1.8) and 8.9 (SD 1.0) for GSTT1 positive cell cultures (n = 13) and 5.3 (SD 1.2) and 12.5 (SD 1.1) for GSTT1 null cell cultures (n = 5) respectively, and the difference between the genotypes was statistically significant (P < 0.001) at the higher dose. All individual mean frequencies of SCEs induced by 250 microM MEB were higher in the GSTT1 null group (range 11.2-13.9) than in the GSTT1 positive group (range 7.2-10.8). The findings suggest that GSTT1, in addition to GSTM1, is involved in the detoxification of MEB in human whole-blood lymphocyte cultures. The deletion of the GSTT1 gene results in reduced erythrocytic detoxification capacity, thereby increasing the genotoxic effects of MEB.
通过对72小时人全血淋巴细胞培养物中姐妹染色单体交换（SCE）的分析，评估了谷胱甘肽S-转移酶T1（GSTT1）基因型对1,3-丁二烯的代谢产物1,2-环氧-3-丁烯（MEB）遗传毒性的影响。培养物来自18名供体，代表GSTT1“阳性”基因型（至少有一个未缺失的GSTT1等位基因；存在GSTT1活性）和GSTT1“无效”基因型（GSTT1基因纯合缺失；无GSTT1活性）。由于我们之前观察到谷胱甘肽S-转移酶M1（GSTM1）的等位基因影响培养淋巴细胞中MEB诱导的SCE，本研究仅纳入了GSTM1无效基因型的个体。在125和250微摩尔MEB（24小时处理48小时）时，GSTT1阳性细胞培养物（n = 13）中MEB诱导的每细胞SCE平均频率（减去对照水平）分别为4.5（标准差1.8）和8.9（标准差1.0），GSTT1无效细胞培养物（n = 5）分别为5.3（标准差1.2）和12.5（标准差1.1），在较高剂量时基因型之间的差异具有统计学意义（P < 0.001）。250微摩尔MEB诱导的所有个体SCE平均频率在GSTT1无效组（范围11.2 - 13.9）高于GSTT1阳性组（范围7.2 - 10.8）。这些发现表明，除了GSTM1之外，GSTT1也参与人全血淋巴细胞培养物中MEB的解毒过程。GSTT1基因缺失导致红细胞解毒能力降低，从而增加了MEB的遗传毒性作用。
