Isolation and characterization of N7-guanyl adducts derived from 1,2-dibromo-3-chloropropane.
1,2-Dibromo-3-chloropropane is a potent renal and testicular toxicant and has been shown to induce tumor formation in laboratory animals. The toxic effects of the compound are thought to be a result of a bioactivation step in which a glutathione conjugate is formed and subsequently reacts with cellular DNA. The L-glutathione conjugate of 1,2-dibromo-3-chloropropane was chemically synthesized and used to alkylate DNA: following incubations of the conjugate with calf thymus DNA and neutral thermal hydrolysis (to release N7-guanyl adducts) four major fluorescent products were observed. Three of these were isolated and characterized, the structures being determined as S-[bis(N7-guanylmethyl)methyl]glutathione and the two diastereomers of S-[1-(hydroxymethyl)-2-(N7-guanyl)ethyl]glutathione. The fourth fluorescent product was unstable and formed in low yield and thus could not be characterized. The formation of these N7-guanyl adducts can be explained by a mechanism that includes the formation of two consecutive episulfonium ion intermediates followed by nucleophilic attack at the unsubstituted methylene carbon. These adducts bear structural and mechanistic similarities to the major adduct derived from 1,2-dibromoethane, S-[2-(N7-guanyl)ethyl]glutathione. The same adducts were also formed when DBCP was incubated with rat liver cytosol, GSH, and DNA. In vivo experiments with DBCP yielded very low levels of the N7-guanyl adducts formed in rat liver compared to the levels seen after treatments with 1,2-dibromoethane. The bis-guanyl adduct represents a cross-linked structure that may be important in the toxicity of this compound. The conjugate was not found to be mutagenic to Salmonella typhimurium TA100 but rather showed a toxic effect toward the bacteria.
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Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
Kim
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Guengerich
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D000818:Animals; D004247:DNA / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D005978:Glutathione / Q000378:metabolism*; D007306:Insecticides / Q000378:metabolism*; D008297:Male; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
D007306:Insecticides; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; D005978:Glutathione; D011407:Propane