title: Formation of 1,N2- and N2,3-ethenoguanine from 2-halooxiranes: isotopic labeling studies and isolation of a hemiaminal derivative of N2-(2-oxoethyl)guanine.
abstract: Vinyl halides are oxidized to 2-halooxiranes, which rapidly rearrange to 2-haloacetaldehydes. Both of these species can react with DNA to generate a variety of adducts, including the potentially mutagenic etheno (epsilon) products. Evidence was provided through kinetic studies that the epsilon-Gua adducts are formed primarily from 2-haloxiranes; consistent with this view, epoxide hydrolase inhibited the formation of N2,3-epsilon-Gua from vinyl chloride but alcohol dehydrogenase did not. Assignments of the NMR shifts of the etheno protons of 1,N2- and N2,3-epsilon-Gua were made with the use of 15N labeling and nuclear Overhauser effects, in revision of the literature. The H-5 proton of N2,3-epsilon-Gua showed facile exchange in acid or base; the H-7 proton of 1,N2-epsilon-Gua was exchanged at neutral or basic pH but not in acid. Reaction of Br2CHCH2OH (labeled at C1 with 2H or 13C) with Guo yielded 1,N2-epsilon-Gua and N2,3-epsilon-Gua, presumably through the intermediacy of 2-bromooxirane. 1H NMR analysis indicated that the labeled carbon was attached to the original Guo N2 atom in both cases. When N2-(2-oxoethyl)Gua was generated from a diethyl acetal or from a glycol, the major product was the cyclic derivative 5,6,7,9-tetrahydro-7-hydroxy-9-oxoimidazo[1,2-alpha]purine. This compound was also formed in considerable yield from the reaction of 2-chlorooxirane with Guo, dGuo 5'-phosphate, or DNA and is relatively stable in the presence of acid or mild base. It does not appear to be readily dehydrated to yield the etheno adducts but may be of significance as a DNA adducts in its own right.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: M
authors.initials: M
authors.lastname: Persmark
authors.forename: W G
authors.initials: WG
authors.lastname: Humphreys
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D007093:Imidazoles / Q000737:chemistry*; D066298:In Vitro Techniques; D007553:Isotope Labeling; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000378:metabolism; D009153:Mutagens / Q000138:chemical synthesis* / Q000633:toxicity; D011687:Purines / Q000737:chemistry*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
chemical_list: D004852:Epoxy Compounds; D007093:Imidazoles; D009153:Mutagens; C015196:N(2),3-ethenoguanine; D011687:Purines; C085535:5,6,7,9-tetrahydro-7-hydroxy-9-oxoimidazo(1,2-a)purine; C085534:1,(N2)-ethenoguanine; D006147:Guanine; C032220:7-N-(2-oxoethyl)guanine; D000426:Alcohol Dehydrogenase; D004851:Epoxide Hydrolases