ROLE OF GSTT1 AND GSTM1 GENOTYPES IN DETERMINING INDIVIDUAL SENSITIVITY TO SISTER-CHROMATID EXCHANGE INDUCTION HY DIEPOXYBUTANE IN CULTUREDHUMAN-LYMPHOCYTES

The individual genotoxic response of cultured human lymphocytes to die poxybutane (DEB), an epoxide metabolite of 1,3-butadiene, shows a bimo dal distribution, Blood donors can be classified as either DEB-sensiti ve or DEB-resistant on the basis of the frequency of sister chromatid exchanges (SCEs) induced by DEB in whole-blood lymphocyte cultures, Th e genetic basis of this phenomenon has thusfar been unknown, To invest igate if differences in the ability of individuals to detoxify DEB cou ld explain the bimodal response, sister chromatid exchanges (SCEs) ind uced by a 48-h treatment with DEB (2 and 5 mu M) were analyzed in whol e-blood lymphocyte cultures of 20 human donors with known genotypes of two polymorphic glutathione S-transferases (GSTs), GSTT1 and GSTM1. B oth polymorphisms include a homozygous null genotype lacking the respe ctive GST gene and isozyme, The mean frequency of SCEs/cell was 1.6 ti mes higher among GSTT1 null donors (n = 8) than GSTT1 positive donors (n = 12) at both 2 mu M DEB (mean 67.3 versus 40.9) and 5 mu M DEB (me an 123.2 versus 77.5), with no overlapping in DEB-induced individual S CE frequencies between the two genotypes, Thus, all DEB-sensitive indi viduals were of the GSTT1 null genotype, while all DEB-resistant perso ns had a detectable GSTT1 gene, A significant (P <0.05) negative corre lation (r = -0.65 at 5 mu M, r = -0.56 at 2 mu M) was obtained in the GSTT1 positive donors between DEB-induced individual SCE frequency and RBC GSTT1 activity, measured by formaldehyde formation from dichlorom ethane; the GSTT1 null individuals showed no GSTT1 activity, At 5 mu M DEB, the lymphocyte cultures of the GSTT1 null donors also had a sign ificantly decreased replication index, indicating an impact of GSTT1 g enotype on the cytotoxicity of DEB, No influence on DEB-induced SCEs o r cytotoxic effects was observed for GSTM1 genotype, It is concluded t hat sensitivity to lit vitro SCE induction by DEB is explained by the lack of GSTT1.