Glutathione S-transferase M1 genotype influences sister chromatid exchange induction but not adaptive response in human lymphocytes treated with 1,2-epoxy-3-butene

Abstract

Induction of sister chromatid exchanges (SCEs) by 1,2-epoxy-3-butene (monoepoxybutene, MEB), an epoxide metabolite of 1,3-butadiene, in human whole-blood lymphocyte cultures has previously been observed to depend on the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genotype of the blood donor. Pretreatment of lymphocyte cultures with a low dose of MEB has been shown to reduce the SCE response obtained by later treatment with a higher concentration of MEB. To investigate whether this adaptive response depends on the GSTM1 genotype of the donor, SCE induction by MEB (25 and 250 μM at 48 h for 24 h) was studied from whole-blood lymphocyte cultures of young non-smoking male and female subjects representing GSTM1 positive (n=7) and null (n=7) genotypes, with or without a MEB pretreatment (12.5 μM at 24 h). A higher mean number of induced SCEs per cell at 250 μM MEB was observed in lymphocytes of the GSTM1 null than positive donors, a statistically significant difference being obtained in the presence of the adaptive treatment (9.44 vs. 6.56; results from ethanol-treated controls subtracted). The pretreatment resulted in a statistically significant reduction in the response of the GSTM1 null group at both concentrations of MEB and in the GSTM1 positive group at 250 μM. However, there were no statistically significant differences in the adaptive response of the two genotypes. In conclusion, the present study further supported earlier findings on an increased sensitivity of GSTM1 null donors to SCE induction by MEB, suggesting that GSTM1 is involved in the detoxification of MEB in human lymphocyte cultures. As an adaptive response was observed in both GSTM1 positive and null donors, the phenomenon cannot be explained by GSTM1 induction. It may represent induction of other enzymes operating in MEB detoxification, or activation of DNA repair.