INFLUENCE OF GSTM1 GENOTYPE ON SISTER-CHROMATID EXCHANGE INDUCTION BYSTYRENE-7,8-OXIDE AND 1,2-EPOXY-3-BUTENE IN CULTURED HUMAN-LYMPHOCYTES

Glutathione S-transferase M1 (GSTM1), catalyzing the conjugation of va rious reactive molecules with glutathione (GSH), shows genetic polymor phism in humans. Almost half of all Caucasians lack the GSTM1 gene, be ing theoretically at a higher risk from the toxic effects of substrate s for GSTM1. The purpose of the present study was to investigate wheth er the GSTM1 genotype of lymphocyte donors influences the in vitro ind uction of sister chromatid exchanges (SCEs) by styrene-7,8-oxide (SO) and 1,2-epoxy-3-butene (MEB), the epoxide metabolites of styrene and b utadiene 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 mu M) and MEB (50 and 250 mu M) were analyzed in cultured (72 h) lymphocytes of six GSTM1 null ( gene deleted) and six GSTM1-positive (gene present) donors, Both SO an d MEB were found to clearly increase SCEs. The GSTM1 genotype had no i nfluence on SCE induction by SO. In contrast, MEB produced a higher le vel of SCEs among the GSTM1 null than GSTM1-positive samples. At 250 I -l-M MEB, the GSTM1 null donors showed 31% more induced SCEs (on avera ge;seven more SCEs per cell) than the GSTM1-positive donors (P = 0.02, acetone treatment as the reference). Furthermore, the GSTM1 null geno type was associated with a slight decrease in mitotic index and replic ation index, regardless of the treatment. The results suggest that GST M1-mediated GSH conjugation is an important detoxification pathway for MEB, but not for SO, in cultured human lymphocytes.