More on genetic predisposition

Abstract

The individual genotoxic response of cultured human lymphocytes to diepoxybutane (DEB), an epoxide metabolite of 1,3-butadiene, shows a bimodal distribution. Blood donors can be classi fied as either DEB-sensitive or DEB-resistant on the basis of the frequency of sister chromatid exchanges (SCEs) induced by DEB in whole-blood lymphocyte cultures. The genetic basis of this phenomenon has thus far been unknown. To investigate if differences in the ability of individuals to detoxify DEB could explain the bimodal response, sister chromatid exchanges (SCEs) induced by a 48-h treatment with DEB (2 and 5 μM were analysed in whole-blood lymphocyte cultures of 20 human donors with known genotypes of two polymorphic glutathione S-transferases (GSTs). GSTT1 and GSTM1. Both polymorphisms include a homozygous null geno type lacking the respective GST gene and isozyme. The mean frequency of SCEs/cell was 1.6 times higher among GSTT1 null donors (n = 8) than GSTT1 positive donors (n = 12) at both 2 μM DEB (mean 67.3 versus 40.9) and 5 μM DEB (mean 123.2 versus 77.5), with no overlapping in DEB-induced individual SCE frequencies between the two geno types. Thus, all DEB-sensitive individuals were of the GSTT1 null genotype, while all DEB-resistant persons had a detectable GSTT1 gene. A significant (P < 0.05) negative correlation (r = -0.65 at 5 μM, r = 0.56 at 2 μM) was obtained in the GSTT1 positive donors between DEB-induced individual SCE fre quency and RBC GSTT1 activity, measured by formaldehyde formation from dichloromethane; the GSTT1 null individuals showed no GSTT1 activity. At 5 μM DEB, the lymphocyte cultures of the GSTT1 null donors also had a significantly decreased repli cation index, indicating an impact of GSTT1 geno type on the cytotoxicity of DEB. No influence on DEB-induced SCEs or cytotoxic effects was observed for GSTM1 genotype. It is concluded that sensitivity to in vitro SCE induction by DEB is explained by the lack of GSTT1.