Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

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• 作者：Melissa Goggin ; Dewakar Sangaraju ; Vernon E. Walker ; Jeffrey Wickliffe ; James A. Swenberg ; Natalia Tretyakova
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：June 20, 2011
• 年：2011
• 卷：24
• 期：6
• 页码：809-817
• 全文大小：895K
• 年卷期：v.24,no.6(June 20, 2011)
• ISSN：1520-5010

文摘

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), N⁶-adenine-N7-guanine cross-links (N⁶A-N7G-BD), and 1,N⁶-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鈭?486). 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鈭?.4 days, 4.6鈭?.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,N⁶-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t_1/2 of 36鈭?2 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,N⁶-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure.