We have developed Salmonella typhimurium strains expressing human glutathione S-transferases (GSTs) to establish the role of these enzymes in chemical activation and deactivation. Alpha and pi class GSTs, GSTA1-1 and GSTP1-1, were expressed in Salmonella TA100 using a regulatable tac promoter expression system. The ability of these GST to modulate the mutagenicity of a range of mutagens including ethylene dibromide, ethylene dichloride and methylene dichloride was then investigated. Ethylene dibromide, ethylene dichloride and methylene dichloride were directly mutagenic in the control TA100 strain. The mutagenicity of ethylene dibromide and ethylene dichloride was increased in cells expressing GSTA1-1, but not in cells expressing GSTP1-1. In contrast, methylene dichloride mutagenicity was unaffected by the presence of either GST. The mutagenicity of 2-aminofluorene, was not altered by the presence of either GST isozyme, while that of N-hydroxy-2-acetylaminofluorene was slightly reduced with both isozymes. The mutagenicity of aflatoxin B1 (AFB1) was marginally decreased in strains expressing GSTP1-1. When GSTA1-1 expression was maximally induced, however, a more pronounced reduction was observed suggesting a role for GSTA1-1 in AFB1 deactivation. The tester strains described here should be valuable in establishing the specificity of human GST isozymes towards chemical toxins and carcinogens, especially for compounds whose reactive intermediates are short lived.

We have expressed human glutathione S-transferases GSTA1-1 and GSTP1-1 in Salmonella typhimurium TA100 in order to assess the ability of these enzymes to modulate the mutagenicity of 1,2-dibromo-3-chloropropane (DBCP) and tris(2,3-dibromopropyl)phosphate (Tris-BP). Both compounds were mutagenic when activated by Aroclor-induced rat liver microsomes. However, when Aroclor-induced rat liver microsomes were used together with the GST-expressing strains the mutagenicity of both DBCP and Tris-BP was markedly potentiated. Neither of the GST-expressing strains potentiated the mutagenicity in the absence of microsomes, indicating that cytochrome P450-mediated metabolism was a prerequisite for GST-mediated potentiation. With DBCP both isozymes had comparable effects on mutagenic frequency, although the highest dose of DBCP was toxic in strains expressing GSTP1-1. In the case of Tris-BP, GSTP1-1 was much more active in potentiating the mutagenicity. These results indicate that human GSTs can play an important role in the activation of compounds such as DBCP and Tris-BP to mutagenic metabolites.