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

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Abstract
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 [ 14 C]EDB (80 μM) 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 (>500 μM) depleted the concentration of hepatocellular glutathione, but binding of [ 14 C]EDB equivalents to nucleic acids occurred at concentrations which had little effect on glutathione levels. Diethylmaleate (750 μM) decreased the binding of [ 14 C]EDB equivalents to nucleic acids by 50%, but SKF-525A (200 μM) did not decrease this binding to nucleic acids. Although both hepatic microsomal and cytosolic fractions catalyzed the covalent binding of [ 14 C]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.