Influence of GSTM1 and GSTT1 genotypes on sister chromatid exchange induction by styrene in cultured human lymphocytes.
Glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) are polymorphically expressed in humans; about 47% and 13% of Finns lack the GSTM1 and GSTT1 activity due to homozygous deletion of the respective genes (null genotypes). We previously observed that GSTT1 null genotype was associated with increased induction of sister chromatid exchanges (SCEs) by a metabolite of styrene, styrene-7,8-oxide, in human lymphocyte cultures, while GSTM1 genotype had no effect. In the present study, we examined the potential effect of these genotypes on SCE induction by the parent compound styrene. Seventy-two hour whole-blood lymphocyte cultures from 24 healthy human donors, representing all different combinations of these genotypes, were examined. In agreement with our earlier findings, styrene was an efficient inducer of SCEs in cultures of all donors. In two separate experiments, the mean number of SCEs/cell induced by 1.5 mM styrene was 1.55 times (P = 0.011) or 1.34 times (P = 0.015) higher in subjects lacking both GSTM1 and GSTT1 than in subjects having both genes. Donors null for only one of the genes showed intermediate SCE induction by styrene. At 0.5 mM styrene, no clear differences in SCE rates among the genotypes were seen. Our results suggest that the concurrent lack of the GSTM1 and GSTT1 genes increases the genotoxic effects of styrene in human cells. The discrepant findings obtained for the importance of GSTM1 genotype in modulating the genotoxic effects induced by styrene-7,8-oxide and styrene may reflect a difference between a direct treatment with styrene-7,8-oxide and its formation from styrene in the cells. Although glutathione conjugation is a minor route in styrene detoxification in human liver in vivo, individual sensitivity associated with GSTM1 and GSTT1 null genotypes may be important locally in blood circulation and in blood-forming organs.
Bernardini
Sabrina
S
Laboratory of Molecular and Cellular Toxicology, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, FIN-00250 Helsinki, Finland.
Hirvonen
Ari
A
Järventaus
Hilkka
H
Norppa
Hannu
H
D002478:Cells, Cultured; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D012854:Sister Chromatid Exchange; D020058:Styrene / Q000633:toxicity*
D005982:Glutathione Transferase; D020058:Styrene; C413545:glutathione S-transferase T1