The bioactivation of 1,2-dibromoethane in rat hepatocytes: covalent binding to nucleic acids.

Isolated rat hepatocytes metabolized 1,2-dibromoethane (EDB) to reactive intermediates which covalently bound to cellular nucleic acids. DNA isolated from hepatocytes that had been incubated with [14C]EDB (80 microM) was alkylated with a specific binding of 0.6 nmol/mg DNA. RNA exhibited a greater specific alkylation with 2.1-3.0 nmol bound/mg. High concentrations of EDB (greater than 500 microM) depleted the concentration of hepatocellular glutathione, but binding of [14C]EDB equivalents to nucleic acids occurred at concentrations which had little effect on glutathione levels. Diethylmaleate (750 microM) decreased the binding of [14C]EDB equivalents to nucleic acids by 50%, but SKF-525A (200 microM) did not decrease this binding to nucleic acids. Although both hepatic microsomal and cytosolic fractions catalyzed the covalent binding of [14C]EDB equivalents to calf thymus DNA, the degree of binding was 12 times greater when cytosolic enzymes were used. The results suggest the involvement of glutathione-S-transferases in the bioactivation of EDB to species that covalently bind to DNA.