Glutathione-mediated binding of dibromoalkanes to DNA: specificity of rat glutathione-S-transferases and dibromoalkane structure.
1,2-Dibromo-[1,2-14C]ethane was bound irreversibly to DNA when glutathione S-transferase or rat liver cytosolic components were added to incubations of calf thymus DNA and glutathione at 37 degrees C. There was no DNA binding of 1,2-dibromoethane when glutathione was absent or in incubations of DNA with microsomal proteins with or without NADPH, thus supporting the proposal that the major route of DNA binding by 1,2-dibromoethane occurs via conjugation to glutathione. In vitro binding of 1,2-dibromoethane occurred most effectively when the YaYc (or 'B') isozyme of glutathione S-transferase was included in incubations of DNA with 1,2-dibromoethane and glutathione. Other dihaloalkanes were incubated with DNA in the presence of glutathione S-transferase and [35S]glutathione. Of these, only 1,2-dibromo-3-chloropropane and tris-(2,3-dibromopropyl)-phosphate led to significant DNA binding of [35S]glutathione. 1,2-Dibromo-3-chloro-[1,3-14C]propane was bound to DNA when glutathione and glutathione S-transferase were present. However, even higher 1,2-dibromo-3-chloropropane binding to DNA occurred when cytosol or microsomes were included in incubations without glutathione. When glutathione was added to incubations containing cytosol and 1,2-dibromo-3-chloropropane, total DNA binding was decreased. Thus, the actual amount of DNA binding by dihaloethanes in vivo may be the result of a complicated balance among the opposing roles of glutathione conjugation in detoxicating and activating processes.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002417:Cattle; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000378:metabolism*; D015946:Ethylene Dibromide / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006842:Hydrocarbons, Brominated / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000378:metabolism; D010755:Organophosphates / Q000378:metabolism; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013950:Thymus Gland
D002273:Carcinogens; D006842:Hydrocarbons, Brominated; D010755:Organophosphates; D011506:Proteins; C012085:tris(2,3-dibromopropyl)phosphate; D015946:Ethylene Dibromide; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; D005982:Glutathione Transferase; D005978:Glutathione; D011407:Propane