Influence of GSTM1 genotype on sister chromatid exchange induction by styrene-7,8-oxide and 1,2-epoxy-3-butene in cultured human lymphocytes.
Glutathione S-transferase M1 (GSTM1), catalyzing the conjugation of various reactive molecules with glutathione (GSH), shows genetic polymorphism in humans. Almost half of all Caucasians lack the GSTM1 gene, being theoretically at a higher risk from the toxic effects of substrates for GSTM1. The purpose of the present study was to investigate whether the GSTM1 genotype of lymphocyte donors influences the in vitro induction of sister chromatid exchanges (SCEs) by styrene-7,8-oxide (SO) and 1,2-epoxy-3-butene (MEB), the epoxide metabolites of styrene and butadiene respectively and potential substrates for GSTM1. SCEs induced after a 48 h treatment (started 24 h after culture initiation) by two different concentrations of SO (50 and 150 microM) and MEB (50 and 250 microM) were analyzed in cultured (72 h) lymphocytes of six GSTM1 null (gene deleted) and six GSTM1-positive (gene present) donors. Both SO and MEB were found to clearly increase SCEs. The GSTM1 genotype had no influence on SCE induction by SO. In contrast, MEB produced a higher level of SCEs among the GSTM1 null than GSTM1-positive samples. At 250 microM MEB, the GSTM1 null donors showed 31% more induced SCEs (on average seven more SCEs per cell) than the GSTM1-positive donors (P = 0.02, acetone treatment as the reference). Furthermore, the GSTM1 null genotype was associated with a slight decrease in mitotic index and replication index, regardless of the treatment. The results suggest that GSTM1-mediated GSH conjugation is an important detoxification pathway for MEB, but not for SO, in cultured human lymphocytes.
Uusküla
M
M
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
Järventaus
H
H
Hirvonen
A
A
Sorsa
M
M
Norppa
H
H
D000328:Adult; D002478:Cells, Cultured; D004852:Epoxy Compounds / Q000633:toxicity*; D005260:Female; D015870:Gene Expression; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000633:toxicity*; D012854:Sister Chromatid Exchange
D004852:Epoxy Compounds; D007527:Isoenzymes; D009153:Mutagens; C024370:3,4-epoxy-1-butene; C013690:styrene oxide; D005982:Glutathione Transferase