title: Persistence and repair of bifunctional DNA adducts in tissues of laboratory animals exposed to 1,3-butadiene by inhalation.
abstract: 1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen. The mechanism of BD-mediated cancer is of significant interest because of the widespread exposure of humans to BD from cigarette smoke and urban air. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is a highly genotoxic and mutagenic bis-alkylating agent believed to be the ultimate carcinogenic species of BD. We have previously identified several types of DEB-specific DNA adducts, including bis-N7-guanine cross-links (bis-N7-BD), N(6)-adenine-N7-guanine cross-links (N(6)A-N7G-BD), and 1,N(6)-dA exocyclic adducts. These lesions were detected in tissues of laboratory rodents exposed to BD by inhalation ( Goggin et al. (2009) Cancer Res. 69 , 2479 -2486 ). In the present work, persistence and repair of bifunctional DEB-DNA adducts in tissues of mice and rats exposed to BD by inhalation were investigated. The half-lives of the most abundant cross-links, bis-N7G-BD, in mouse liver, kidney, and lungs were 2.3-2.4 days, 4.6-5.7 days, and 4.9 days, respectively. The in vitro half-lives of bis-N7G-BD were 3.5 days (S,S isomer) and 4.0 days (meso isomer) due to their spontaneous depurination. In contrast, tissue concentrations of the minor DEB adducts, N7G-N1A-BD and 1,N(6)-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t(1/2) of 36-42 days. No differences were observed between DEB-DNA adduct levels in BD-treated wild type mice and the corresponding animals deficient in methyl purine glycosylase or the Xpa gene. Our results indicate that DEB-induced N7G-N1A-BD and 1,N(6)-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure.
authors: Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors: Melissa
authors: M
authors: Goggin
authors: Dewakar
authors: D
authors: Sangaraju
authors: Vernon E
authors: VE
authors: Walker
authors: Jeffrey
authors: J
authors: Wickliffe
authors: James A
authors: JA
authors: Swenberg
authors: Natalia
authors: N
authors: Tretyakova
mesh_terms: D000393:Air Pollutants / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002070:Butadienes / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair; D004852:Epoxy Compounds / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics
chemical_list: D000393:Air Pollutants; D002070:Butadienes; D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; C007366:diepoxybutane; D004247:DNA; D045647:DNA Glycosylases; C031763:1,3-butadiene