Trans-stilbene oxide-induced sister chromatid exchange in cultured human lymphocytes: influence of GSTM1 and GSTT1 genotypes.
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.
Bernardini
S
S
Laboratory of Molecular and Cellular Toxicology, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 b, FIN-00250 Helsinki, Finland.
Hirvonen
A
A
Järventaus
H
H
Norppa
H
H
D000328:Adult; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012854:Sister Chromatid Exchange; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors
D005982:Glutathione Transferase; D013267:Stilbenes; C413545:glutathione S-transferase T1; C025906:stilbene oxide