Influence of GSTT1 genotype on sister chromatid exchange induction by styrene-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 response to genotoxic carcinogens. We have previously shown that donor GSTM1 genotype does not influence the induction of sister chromatid exchanges (SCEs) in cultured human lymphocytes by styrene-7,8-oxide (SO), a metabolite of styrene. Here, we expanded the study to GSTT1 polymorphism. SCEs were analyzed from 72-hr whole-blood lymphocyte cultures of five GSTT1 positive (at least one undeleted allele) and five GSTT1 null (gene homozygously deleted) donors, all GSTM1 positive, after a 48-hr treatment with 50 microM and 150 microM 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 microM) and 1.4 (150 microM) times greater among the GSTT1 null individuals (4.83 at 50 microM, 18.98 at 150 microM) compared with the GSTT1 positive individuals (2.78 at 50 microM, 13.74 at 150 microM), the differences being statistically significant (P=0.006 and P=0.022, respectively). These findings show that the lack of the GSTT1 gene increases the genotoxic effects of SO in human whole-blood lymphocyte cultures, suggesting that GSTT1 is involved in the detoxification of SO in humans. Although glutathione conjugation is considered a minor metabolic pathway for SO in vivo, the high GSTT1 activity in erythrocytes may be important locally and might affect the level of genotoxic damage observed in peripheral lymphocytes of styrene-exposed reinforced plastics workers. The GSTT1 polymorphism could also influence the urinary excretion of SO-specific mercapturic acids.
Ollikainen
T
T
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
Hirvonen
A
A
Norppa
H
H
D000328:Adult; D002478:Cells, Cultured; D004852:Epoxy Compounds / Q000494:pharmacology*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D012854:Sister Chromatid Exchange
D004852:Epoxy Compounds; D009153:Mutagens; C013690:styrene oxide; D005982:Glutathione Transferase