METABOLISM OF 1,2-DIBROMO-3-CHLOROPROPANE BY GLUTATHIONE S-TRANSFERASES

The metabolism of 1,2-dibromo-3-chloropropane (DBCP), measured as the formation of water soluble metabolites and metabolites covalently boun d to macromolecules, was studied in isolated rat liver, kidney, and te sticular cells, in subcellular fractions, and with purified rat and hu man glutathione S-transferases (GSTs). The rate of formation of water soluble metabolites in the cells were in the order liver > kidney > te stis. The rate of covalent macromolecular binding of reactive DBCP met abolites in the different cell types was of the same relative order, P retreatment of the cells with the GSH depleting agent diethyl maleate (DEM) markedly decreased the rate of covalent binding in all cell type s, Both the overall metabolism and the formation of DBCP metabolites t hat covalently bound to macromolecules, were substantially higher in r at testicular cells compared to hamster testicular cells. Rat liver cy tosol and microsomes, and various purified rat and human GSTs extensiv ely metabolized DBCP to water soluble metabolites in the presence of G SH. When compared to isolated cells, substantially lower rates of bind ing per mg protein could be observed in subcellular fractions, Binding of DBCP was detected in the microsomal and cytosolic fractions in the absence of NADPH, though in microsomes fortified with a NADPH-regener ating system, the generation of reactive DBCP metabolites was approxim ately doubled. Studies with purified rat GST isozymes showed that the relative overall GSH conjugation activity with DBCP was in the followi ng order: GST form 3-3 > 2-2 approximate to 12-12 > 1-1 > 4-4 approxim ate to 8-8 approximate to 7-7. Furthermore, human GST forms also readi ly metabolized DBCP with activities of GST A1-2 > A2-2 approximate to A1-1 > M1a-1a > M3-3 approximate to P1-1.