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.
D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D004247:DNA / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006842:Hydrocarbons, Brominated / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009153:Mutagens / Q000378:metabolism*; D011335:Proadifen / Q000494:pharmacology; D012313:RNA / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D006842:Hydrocarbons, Brominated; D009153:Mutagens; D012313:RNA; D004247:DNA; D011335:Proadifen; D005978:Glutathione; C027947:methylene bromide