INFLUENCE OF GSTT1 GENOTYPE ON SISTER-CHROMATID EXCHANGE INDUCTION BYSTYRENE-7,8-OXIDE IN CULTURED HUMAN-LYMPHOCYTES

The genetic polymorphisms of glutathione S-transferases (GSTs), which are involved in the metabolic inactivation of various toxicants, have been suggested to be an important source of variation in individual re sponse to genotoxic carcinogens. We have previously shown that donor G STM1 genotype does not influence the induction of sister chromatid exc hanges (SCEs) in cultured human lymphocytes by styrene-7,8-oxide (SO), a metabolite of styrene. Here, we expanded the study to GSTT1 polymor phism. SCEs were analyzed From 72-hr whole-blood lymphocyte cultures o f Five GSTT1 positive (at least one undeleted allele) and five GSTT1 n ull (gene homozygously deleted) donors, all GSTM1 positive, after a 48 -hr treatment with 50 mu M and 150 mu M SO. SO clearly increased SCEs in cultures of all donors. The mean number of SCEs/cell induced by SO (individual mean SCEs from acetone-treated control cultures subtracted ) was 1.7 (50 mu M) and 1.4 (150 mu M) times greater among the GSTT1 n ull individuals (4.83 at 50 mu M, 18.98 ai 150 mu M) compared with the GSTT1 positive individuals (2.78 at 50 mu M, 13.74 at 150 mu M), the differences being statistically significant (P = 0.006 and P = 0.022, respectively). These findings show that the lack of the GSTT1 gene inc reases the genotoxic effects of SO in human whole-blood lymphocyte cul tures, suggesting that GSTT1 is involved in the detoxification of SO i n humans. Although glutathione conjugation is considered a minor metab olic pathway for SO in vivo, the high GSTT1 activity in erythrocytes m ay be important locally and might affect the level of genotoxic damage observed in peripheral lymphocytes of styrene-exposed reinforced plas tics workers. The GSTT1 polymorphism could also influence the urinary excretion of SO-specific mercapturic acids. (C) 1998 Wiley-Liss, inc.