Home LiteratureArticle Details
PMID: 16022506 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Guanine-specific oxidation of double-stranded DNA by Cr(VI) and ascorbic acid forms spiroiminodihydantoin and 8-oxo-2'-deoxyguanosine.

Chemical research in toxicology ·Vol. 18 ·No. 7 ·2005-07-00 ·Pages 1140-9

Slade PG, Hailer MK, Martin BD, Sugden KD

Abstract

7,8-dihydro-8-oxoguanine (8-oxoG) is thought to be a major lesion formed in DNA by oxidative attack at the nucleobase guanine. Recent studies have shown that 8-oxoG has a lower reduction potential than the parent guanine and is a hot spot for further oxidation. Spiroiminodihydantoin (Sp) has been identified as one of these further oxidation products. Chromium(VI) is a human carcinogen that, when reduced by a cellular reductant such as ascorbate, can oxidize DNA. In this study, duplex DNA was reacted with Cr(VI) and ascorbate to identify and quantify the base lesions formed. Guanine bases were observed to be preferentially oxidized with 5' guanines within purine repeats showing enhanced oxidation. Trapping of the guanine lesions by the base excision repair enzymes hOGG1 and mNEIL2 showed nearly exclusive trapping by mNEIL2, suggesting that 8-oxoG was not the major lesion but rather a lesion recognized by mNEIL2 such as Sp. Formation of the Sp lesion in the Cr(VI)/Asc oxidation reaction with DNA was confirmed by LC-ESI-MS detection. HPLC-ECD was used to identify and quantify any 8-oxoG arising from Cr(VI)/Asc oxidation of DNA. Concentrations of Cr(VI) (3.1-50 microM) with a corresponding 1:10 ratio of Asc oxidized between 0.3% and 1.5% of all guanines within the duplex DNA strand to Sp. 8-oxoG was also identified but with the highest Cr(VI) concentration converting approximately 0.1% of all guanines to 8-oxoG. These results show that Sp was present in concentrations approximately 20 times greater than that of 8-oxoG in this system. The results indicate that 8-oxoG, while present, was not the major product of Cr(VI)/Asc oxidation of DNA and that Sp predominates under these conditions. These results further imply that Sp may be the lesion that accounts for the carcinogenicity of this metal in cellular systems.

MeSH Terms
8-Hydroxy-2'-Deoxyguanosine Ascorbic Acid/chemistry,pharmacology Chromium/chemistry,pharmacology DNA/chemistry,metabolism DNA Glycosylases/metabolism DNA Repair Deoxyguanosine/analogs & derivatives,chemistry,metabolism Guanine/chemistry,metabolism Guanosine/analogs & derivatives,chemistry,metabolism Molecular Structure Oxidation-Reduction/drug effects Spectrometry, Mass, Electrospray Ionization Spiro Compounds/chemistry,metabolism
Chemicals
Spiro Compounds spiroiminodihydantoin Chromium Guanosine Guanine 8-Hydroxy-2'-Deoxyguanosine DNA DNA Glycosylases Deoxyguanosine Ascorbic Acid
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Slade Peter G
Department of Chemistry, The University of Montana, Missoula, Montana 59812, USA.
Hailer M Katie
Martin Brooke D
Sugden Kent D
References (46)
46 references, click to expand
  1. Effects of Cr(VI) on the expression of the oxidative stress genes in human lung cells.
    Carcinogenesis. 1998 Aug;19(8):1401-7 PMID: 9744536
  2. Oxidants, antioxidants, and the degenerative diseases of aging.
    Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7915-22 PMID: 8367443
  3. Long-range DNA charge transport.
    J Org Chem. 2003 Aug 22;68(17):6475-83 PMID: 12919006
  4. Formation of 13C-, 15N-, and 18O-labeled guanidinohydantoin from guanosine oxidation with singlet oxygen. Implications for structure and mechanism.
    J Am Chem Soc. 2003 Nov 19;125(46):13926-7 PMID: 14611206
  5. The human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) DNA repair enzyme and its association with lung cancer risk.
    Pharmacogenetics. 2004 Feb;14(2):103-9 PMID: 15077011
  6. Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: role of a Cr(IV)-mediated Fenton-like reaction.
    Carcinogenesis. 1994 Nov;15(11):2475-8 PMID: 7955094
  7. Characterization of spiroiminodihydantoin as a product of one-electron oxidation of 8-Oxo-7,8-dihydroguanosine.
    Org Lett. 2000 Mar 9;2(5):613-6 PMID: 10814391
  8. Mutational specificity in a shuttle vector replicating in chromium(VI)-treated mammalian cells.
    Environ Mol Mutagen. 1999;33(4):313-9 PMID: 10398379
  9. Gel electrophoretic detection of 7,8-dihydro-8-oxoguanine and 7, 8-dihydro-8-oxoadenine via oxidation by Ir (IV).
    Nucleic Acids Res. 1998 May 1;26(9):2247-9 PMID: 9547288
  10. Reaction of chromium(VI) with ascorbate produces chromium(V), chromium(IV), and carbon-based radicals.
    Chem Res Toxicol. 1994 Mar-Apr;7(2):219-30 PMID: 8199312
  11. Ab initio molecular orbital study on the G-selectivity of GGG triplet in copper(I)-mediated one-electron oxidation.
    J Am Chem Soc. 2003 Feb 19;125(7):1968-74 PMID: 12580624
  12. Reaction of singlet oxygen with 2'-deoxyguanosine and DNA. Isolation and characterization of the main oxidation products.
    Chem Res Toxicol. 1995 Apr-May;8(3):379-88 PMID: 7578924
  13. Chromium(VI) exposure enhances polycyclic aromatic hydrocarbon-DNA binding at the p53 gene in human lung cells.
    Carcinogenesis. 2003 Apr;24(4):771-8 PMID: 12727806
  14. Single extraction protocol for the analysis of 8-hydroxy-2'-deoxyguanosine (oxo8dG) and the associated activity of 8-oxoguanine DNA glycosylase.
    J Neurosci Methods. 2004 Jun 15;136(1):69-76 PMID: 15126047
  15. The pH-dependent role of superoxide in riboflavin-catalyzed photooxidation of 8-oxo-7,8-dihydroguanosine.
    Org Lett. 2001 Sep 6;3(18):2801-4 PMID: 11529760
  16. Recognition of the oxidized lesions spiroiminodihydantoin and guanidinohydantoin in DNA by the mammalian base excision repair glycosylases NEIL1 and NEIL2.
    DNA Repair (Amst). 2005 Jan 2;4(1):41-50 PMID: 15533836
  17. DNA glycosylases in the base excision repair of DNA.
    Biochem J. 1997 Jul 1;325 ( Pt 1):1-16 PMID: 9224623
  18. Binding of chromium to chromatin and DNA from liver and kidney of rats treated with sodium dichromate and chromium(III) chloride in vivo.
    Cancer Res. 1985 Mar;45(3):1146-51 PMID: 2578874
  19. The reduction of chromium (VI) to chromium (III) by glutathione: an intracellular redox pathway in the metabolism of the carcinogen chromate.
    Toxicology. 1984 Dec;33(3-4):341-8 PMID: 6515663
  20. Oxidative Nucleobase Modifications Leading to Strand Scission.
    Chem Rev. 1998 May 7;98(3):1109-1152 PMID: 11848927
  21. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG.
    Nature. 1991 Jan 31;349(6308):431-4 PMID: 1992344
  22. Deferoxamine inhibition of Cr(V)-mediated radical generation and deoxyguanine hydroxylation: ESR and HPLC evidence.
    Arch Biochem Biophys. 1992 Mar;293(2):281-6 PMID: 1311164
  23. Chromium (VI)-induced DNA damage in chick embryo liver and blood cells in vivo.
    Carcinogenesis. 1986 Dec;7(12):2085-8 PMID: 3779902
  24. Effect of ascorbic acid on DNA damage, cytotoxicity, glutathione reductase, and formation of paramagnetic chromium in Chinese hamster V-79 cells treated with sodium chromate(VI).
    J Biol Chem. 1991 Feb 25;266(6):3383-6 PMID: 1847372
  25. In vitro nucleotide misinsertion opposite the oxidized guanosine lesions spiroiminodihydantoin and guanidinohydantoin and DNA synthesis past the lesions using Escherichia coli DNA polymerase I (Klenow fragment).
    Biochemistry. 2002 Dec 24;41(51):15304-14 PMID: 12484769
  26. Characterization of DNA-protein complexes induced in intact cells by the carcinogen chromate.
    Mol Carcinog. 1988;1(2):125-33 PMID: 3151260
  27. Cloning of a yeast 8-oxoguanine DNA glycosylase reveals the existence of a base-excision DNA-repair protein superfamily.
    Curr Biol. 1996 Aug 1;6(8):968-80 PMID: 8805338
  28. Hypervalent chromium mimics reactive oxygen species as measured by the oxidant-sensitive dyes 2',7'-dichlorofluorescin and dihydrorhodamine.
    Chem Res Toxicol. 1998 Dec;11(12):1402-10 PMID: 9860481
  29. Analysis of the induction of alkali sensitive sites in the DNA by chromate and other agents that induce single strand breaks.
    Carcinogenesis. 1984 Sep;5(9):1207-9 PMID: 6467509
  30. Oxidation of 7,8-dihydro-8-oxoguanine affords lesions that are potent sources of replication errors in vivo.
    Biochemistry. 2002 Jan 22;41(3):914-21 PMID: 11790114
  31. DNA lesions derived from the site selective oxidation of Guanine by carbonate radical anions.
    Chem Res Toxicol. 2003 Dec;16(12):1528-38 PMID: 14680366
  32. Analysis of metal-induced DNA lesions and DNA-repair replication in mammalian cells.
    Mutat Res. 1984 Mar-Apr;131(3-4):173-81 PMID: 6717471
  33. Peroxynitrite-induced reactions of synthetic oligonucleotides containing 8-oxoguanine.
    Chem Res Toxicol. 1999 May;12(5):459-66 PMID: 10328757
  34. Base-specific arrest of in vitro DNA replication by carcinogenic chromium: relationship to DNA interstrand crosslinking.
    Carcinogenesis. 1994 Nov;15(11):2421-7 PMID: 7955085
  35. Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI).
    Chem Res Toxicol. 2005 Jan;18(1):3-11 PMID: 15651842
  36. The hydantoin lesions formed from oxidation of 7,8-dihydro-8-oxoguanine are potent sources of replication errors in vivo.
    Biochemistry. 2003 Aug 12;42(31):9257-62 PMID: 12899611
  37. Direct oxidation of guanine and 7,8-dihydro-8-oxoguanine in DNA by a high-valent chromium complex: a possible mechanism for chromate genotoxicity.
    Chem Res Toxicol. 2001 Sep;14(9):1315-22 PMID: 11559048
  38. Mmh/Ogg1 gene inactivation results in accumulation of 8-hydroxyguanine in mice.
    Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4156-61 PMID: 10725358
  39. Age-related and tissue-specific accumulation of oxidative DNA base damage in 7,8-dihydro-8-oxoguanine-DNA glycosylase (Ogg1) deficient mice.
    Carcinogenesis. 2001 Sep;22(9):1459-63 PMID: 11532868
  40. Two pathways for chromium(VI)-induced DNA damage in 14 day chick embryos: Cr-DNA binding in liver and 8-oxo-2'-deoxyguanosine in red blood cells.
    Carcinogenesis. 1994 Dec;15(12):2911-7 PMID: 8001255
  41. Mutagenesis by 8-oxoguanine: an enemy within.
    Trends Genet. 1993 Jul;9(7):246-9 PMID: 8379000
  42. Genotoxicity and mutagenicity of chromium(VI)/ascorbate-generated DNA adducts in human and bacterial cells.
    Biochemistry. 2003 Feb 4;42(4):1062-70 PMID: 12549927
  43. Recent aspects of oxidative DNA damage: guanine lesions, measurement and substrate specificity of DNA repair glycosylases.
    Biol Chem. 2002 Jun;383(6):933-43 PMID: 12222683
  44. Ascorbate is the principal reductant of chromium (VI) in rat liver and kidney ultrafiltrates.
    Carcinogenesis. 1991 Sep;12(9):1733-7 PMID: 1893533
  45. Insertion of dGMP and dAMP during in vitro DNA synthesis opposite an oxidized form of 7,8-dihydro-8-oxoguanine.
    Nucleic Acids Res. 1999 Jan 15;27(2):496-502 PMID: 9862971
  46. Guanine and 7,8-dihydro-8-oxo-guanine-specific oxidation in DNA by chromium(V).
    Environ Health Perspect. 2002 Oct;110 Suppl 5:725-8 PMID: 12426120
Article Info
Journal
Chemical research in toxicology
Abbr.
Chem Res Toxicol
ISSN
0893-228X
DOI
10.1021/tx050033y
Published
2005-07-00
Pages
1140-9
Language
English
Region
United States
NLM ID
8807448
PMCID
PMC1305915
Subset
IM
Grants
NCRR NIH HHS · P20 RR017670 · United States
NIEHS NIH HHS · R01 ES010437 · United States
NIEHS NIH HHS · ES10437 · United States
NCRR NIH HHS · P20RR017670 · United States
External Links
PubMed source DOI: 10.1021/tx050033y PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2