title: 1,N2-propanodeoxyguanosine adducts of the 1,3-butadiene metabolite, hydroxymethylvinyl ketone.
abstract: 1,3-Butadiene (BD) is a rodent and human carcinogen. While several epoxides formed during BD metabolism are mutagenic and may contribute to BD carcinogenicity, another proposed metabolite, hydroxymethylvinyl ketone (HMVK), could also be involved. A significant quantity of HMVK is likely to be formed since it is a proposed intermediate in the metabolism of 3-butene-1,2-diol (BD-diol) to 1,2-dihydroxy-4-(N-acetylcysteinyl)butane, the major mercapturic acid metabolite of BD in humans. In addition, BD-diol is a major BD metabolite in liver perfusion experiments in rodents. By analogy with other alpha,beta-unsaturated carbonyls, HMVK is likely to be mutagenic via formation of promutagenic 1,N(2)-propanodeoxyguanosine adducts. The objective of the current study was to investigate the formation of such adducts in vitro. The reaction between HMVK and dGuo yielded two major products shown to be identical by positive ion electrospray-MS, having protonated molecular ions with m/z consistent with HMVK-derived 1,N(2)-propanodeoxyguanosine (HMVK-dGuo). Rechromatography of each fraction yielded two fractions with retention times identical to those initially isolated, suggesting equilibration between two diastereomers. Two partially resolved sets of (1)H NMR signals were consistent with a 1:1 mixture of diastereomeric C-6-substituted adducts equilibrating slowly on an NMR time-scale. Following deglycosylation, C-6 substitution was verified by two-dimensional correlation NMR spectroscopy, indicating that the initial adducts were formed by Michael addition of dGuo-N1 to the terminal vinyl carbon followed by cyclization to the 1,N(2)-propano structure. Reactions with calf thymus DNA under physiological conditions yielded two sets of products. The first set had HPLC retention times and mass spectra identical to those of the previously characterized C-6-substituted HMVK-dGuo diastereomers. The second set had a molecular ion and fragmentation pattern identical to the C-6-substituted adducts and on this basis were assigned as the diastereomeric C-8 adducts. In addition to detecting HMVK-dGuo in treated DNA, the adducts were also present in control DNA. Overall, our research demonstrates that HMVK can form promutagenic DNA adducts and it therefore has the potential to play a role in BD-associated mutagenicity.
authors: Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7400, USA.
authors: Mark W
authors: MW
authors: Powley
authors: Karupiah
authors: K
authors: Jayaraj
authors: Avram
authors: A
authors: Gold
authors: Louise M
authors: LM
authors: Ball
authors: James A
authors: JA
authors: Swenberg
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002074:Butanones / Q000737:chemistry / Q000378:metabolism*; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D005544:Forecasting; D006801:Humans
chemical_list: C076892:1,2-dihydroxy-4-(N-acetylcysteinyl)butane; D002070:Butadienes; D002074:Butanones; D002273:Carcinogens; D018736:DNA Adducts; C495785:hydroxymethylvinyl ketone; C060934:1,N(2)-propanodeoxyguanosine; D004247:DNA; C427203:calf thymus DNA; C057920:3-buten-2-one; D003849:Deoxyguanosine; C031763:1,3-butadiene; D000111:Acetylcysteine