title: Site-specific mutagenicity of stereochemically defined 1,N2-deoxyguanosine adducts of trans-4-hydroxynonenal in mammalian cells.
abstract: Trans-4-hydroxynonenal (HNE) is a toxic compound produced endogenously during lipid peroxidation. HNE is a potent electrophile that is reactive with both proteins and nucleic acids. HNE preferentially reacts with deoxyguanosine to form four stereoisomeric HNE-deoxyguanosine (HNE-dG) adducts: (6R, 8S, 11R), (6S, 8R, 11S), (6R, 8S, 11S), and (6S, 8R, 11R). These adducts were synthesized into 12-mer oligodeoxynucleotides, inserted into a DNA shuttle vector and evaluated for the ability of each stereoisomer to induce mutagenesis when replicated through mammalian cells. The resultant mutagenicity of these adducts was related to their stereochemistry, in that two of the HNE-dG adducts, (6R, 8S, 11R) and (6S, 8R, 11S), were significantly more mutagenic than the (6R, 8S, 11S) and (6S, 8R, 11R) HNE-dG adducts. These data conclusively demonstrate that HNE-derived DNA adducts can be mutagenic in mammalian cells and their ability to cause mutations is dictated by their stereochemistry.
authors.affiliation: Sealy Center for Molecular Science and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Priscilla H
authors.initials: PH
authors.lastname: Fernandes
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Carmelo J
authors.initials: CJ
authors.lastname: Rizzo
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D019556:COS Cells; D006224:Cricetinae; D018736:DNA Adducts; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity*; D016297:Mutagenesis, Site-Directed; D013237:Stereoisomerism
chemical_list: C117629:8-nitro-2'-deoxyguanosine; D000447:Aldehydes; D018736:DNA Adducts; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal