Müller M, Krämer A, Angerer J, Hallier E
Abteilung Arbeits-und Sozialmedizin der Georg-August-Universität Göttingen, Germany.
Int Arch Occup Environ Health. 1998 Oct;71(7):499-502. doi: 10.1007/s004200050312.
The influence of the polymorphic human glutathione-S-transferase (GST) T1 and M1 genotypes (classified as "conjugators" and "nonconjugators") on the biological effects of nonoccupational ethylene oxide exposure as reflected by the formation of globin N2-hydroxyethylvaline adducts was investigated. Specific attention was paid to smoking as a potential source of exposure. A total of 27 Caucasian subjects, including 10 women and 17 men, participated in the study. Volunteers were grouped as smokers, i.e., 6 subjects (5 male, 1 female), and nonsmokers, i.e., 21 subjects (12 male, 9 female). The regular cigarette consumption in the smoker group ranged from 10 to 25 cigarettes/day.
The amount of N2-hydroxyethylvaline (HEV) bound to the N-terminal valine in human globin was determined following a procedure described by Bader and co-workers and the Deutsche Forschungsgemeinschaft. The GST genotypes were determined by a polymerase chain reaction (PCR) analysis outlined by Bell and colleagues (with beta-globin serving as an internal standard) and Kempkes and co-workers (coamplification of the GSTT1 fragment).
The median level of HEV detected in the smoker group was 280 pmol/g globin as compared with the median value of 50 pmol/g globin recorded for the nonsmokers, indicating that ethylene oxide intake from cigarettes may result in a approximately 5-fold higher overall HEV level in smokers in comparison with nonsmoking individuals. No dose-effect correlation was observed between daily cigarette consumption and the resulting HEV levels. Moreover, the individual GSTT1 or GSTM1 genotype did not influence the HEV level in smokers. The subgroup of nonsmoking GSTT1 conjugators revealed a median HEV value of 46 pmol/g globin as compared with the median value of 92 pmol/g globin found in the nonconjugator subgroup. Subjects with the GSTM1 gene had a median HEV value of 55 pmol/g globin, whereas subjects with the gene deletion had a median HEV value of 44 pmol/g globin. The 2-fold increase in the median HEV value detected in GSTT1 non-conjugators as compared with GSTTI conjugators indicates an influence of GSTT1 on the globin HEV levels. This hypothesis was found to be significant in the nonparametric Mann-Whitney U-test for independent samples (P < 0.002, two-sided). The same test was applied to evaluate the influence of GSTM1 on the globin HEV levels. No significant influence was observed (P > 0.10; two-sided).
This result is in accordance with the finding that ethylene oxide is a substrate for GSTT1 but not for GSTM1. In addition, this study demonstrates a clear influence of genetically determined GSTT1 status on biological effects, e.g., protein adduct formation after non-occupational ethylene oxide exposure. In smokers, however, a modulating influence of GSTT1 status was not observed.
研究多态性人类谷胱甘肽 - S - 转移酶（GST）T1和M1基因型（分为“结合剂”和“非结合剂”）对非职业性环氧乙烷暴露生物效应的影响，该效应通过珠蛋白N2 - 羟乙基缬氨酸加合物的形成来反映。特别关注吸烟作为潜在暴露源的情况。共有27名白种人受试者参与了该研究，其中包括10名女性和17名男性。志愿者被分为吸烟者，即6名受试者（5名男性，1名女性），和非吸烟者，即21名受试者（12名男性，9名女性）。吸烟组的常规香烟消费量为每天10至25支。
按照Bader及其同事以及德国研究联合会描述的程序，测定与人类珠蛋白N端缬氨酸结合的N2 - 羟乙基缬氨酸（HEV）的量。通过Bell及其同事（以β - 珠蛋白作为内标）以及Kempkes及其同事（GSTT1片段的共扩增）概述的聚合酶链反应（PCR）分析来确定GST基因型。
吸烟组中检测到的HEV中位数水平为280 pmol/g珠蛋白，而非吸烟者记录的中位数为50 pmol/g珠蛋白，这表明香烟中的环氧乙烷摄入量可能使吸烟者的总体HEV水平比非吸烟个体高约5倍。未观察到每日香烟消费量与由此产生的HEV水平之间的剂量 - 效应相关性。此外，个体GSTT1或GSTM1基因型不影响吸烟者的HEV水平。非吸烟GSTT1结合剂亚组的HEV中位数为46 pmol/g珠蛋白，而非结合剂亚组为92 pmol/g珠蛋白。具有GSTM1基因的受试者的HEV中位数为55 pmol/g珠蛋白，而基因缺失的受试者的HEV中位数为44 pmol/g珠蛋白。与GSTTI结合剂相比，GSTT1非结合剂中检测到的HEV中位数增加了2倍，表明GSTT1对珠蛋白HEV水平有影响。在独立样本的非参数Mann - Whitney U检验中发现该假设具有显著性（P < 0.002，双侧）。应用相同的检验来评估GSTM1对珠蛋白HEV水平的影响。未观察到显著影响（P > 0.10；双侧）。
该结果与环氧乙烷是GSTT1的底物而非GSTM1的底物这一发现一致。此外，本研究表明遗传决定的GSTT1状态对生物效应有明显影响，例如非职业性环氧乙烷暴露后的蛋白质加合物形成。然而，在吸烟者中未观察到GSTT1状态的调节作用。
