DNA Damage and Nitric Oxide

  • Larry K. Keefer
  • David A. Wink
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


While there is no evidence that nitric oxide (NO) reacts directly with DNA, NO can modify the biopolymer by a variety of indirect pathways. In this review, we describe a selection of the reported mechanisms by which exposure to NO might affect the integrity of DNA, with emphasis on the biological reactive intermediates (BRIs) capable of participating in such transformations.


Nitric Oxide Ribonucleotide Reductase Tyrosyl Radical Damage Fixation Aerobic Solution 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Butler, A.R., and Williams, D.L.H. 1993, The physiological role of nitric oxide, Chem. Soc. Rev. 22: 233–241.CrossRefGoogle Scholar
  2. Ford, P.C., Wink, D.A., and Stanbury, D.M. 1993, Autoxidation kinetics of aqueous nitric oxide, FEBS Lett. 326: 1–3.PubMedCrossRefGoogle Scholar
  3. Görsdorf, S., Appel, K.E., Engeholm, C, and Obe, G. 1990, Nitrogen dioxide induces DNA single-strand breaks in cultured Chinese hamster cells, Carcinogenesis 11: 37–41.PubMedCrossRefGoogle Scholar
  4. Huie, R.E., and Padmaja, S. 1993, The reaction of NO with Superoxide, Free Radical Res. Commun. 18: 195–199.CrossRefGoogle Scholar
  5. Ignarro, L.J., Fukuto, J.M., Griscavage, J.M., Rogers, N.E., and Byrns, R.E. 1993, Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: Comparison with enzymatically formed nitric oxide from L-arginine, Proc. Natl. Acad. Sci. (USA) 90: 8103–8107.CrossRefGoogle Scholar
  6. Kanner, J., Harel, S., and Granit, R. 1991, Nitric oxide as an antioxidant, Arch. Biochem. Biophvs. 289: 130–136.CrossRefGoogle Scholar
  7. Karupiah, G., Xie, Q.-w., Buller, R.M.L., Nathan, C, Duarte, C, and MacMicking, J.D. 1993, Inhibition of viral replication by interferon-γ-induced nitric oxide synthase, Science 261: 1445–1448.PubMedCrossRefGoogle Scholar
  8. Khatsenko, O.G., Gross, S.S, Rifkind, A.B., and Vane, J.R. 1993, Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants, Proc. Natl. Acad. Sci. (USA) 90: 11147–11151.CrossRefGoogle Scholar
  9. Kirchner, J.J., and Hopkins, P.B. 1991, Nitrous acid cross-links duplex DNA fragments through deoxyguanosme residues at the sequence 5’-CG, J. Am. Chem. Soc. 113: 4681–4682.CrossRefGoogle Scholar
  10. Koppenol, W.H., Moreno, J.J., Pryor, W.A., Ischiropoulos, H., and Beckman, J.S. 1992, Peroxynitrite, a cloaked oxidant formed by nitric oxide and Superoxide, Chem. Res. Toxicol. 5: 834–842.PubMedCrossRefGoogle Scholar
  11. Laval, F., and Wink, D.A. 1994, Inhibition by nitric oxide of the repair protein, O 6-methylguanine-DNA-methyltransferase, Carcinogenesis 15: 443–447.PubMedCrossRefGoogle Scholar
  12. Leaf, C.D., Wishnok, J.S., and Tannenbaum, S.R. 1991, Endogenous incorporation of nitric oxide from L-arginine into N-nitrosomorpholine stimulated by Escherichia coli lipopolysaccharide in the rat, Carcinogenesis 12: 537–539.PubMedCrossRefGoogle Scholar
  13. Lepoivre, M., Flaman, J.-M., and Henry, Y. 1992, Early loss of the tyrosyl radical in ribonucleotide reductase of adenocarcinoma cells producing nitric oxide, J. Biol. Chem. 267: 22994–23000.PubMedGoogle Scholar
  14. Liebmann, J., De Luca, A.M., Coffin, D., Wink, D.A., Keefer, L.K., and Mitchell, J.B., 1994, In vivo radioprotection of normal tissue with tumor radiosensitization by nitric oxide, Proc. Am. Assoc. Cancer Res. 35: 649 (abstract 3868).Google Scholar
  15. Mitchell, J.B., Wink, D.A., De Graff, W., Gamson, J., Keefer, L.K., and Krishna, M.C. 1993, Hypoxie mammalian cell radiosensitization by nitric oxide, Cancer Res. 53: 5845–5848.PubMedGoogle Scholar
  16. Nelson, D.R., Kamataki, T., Waxman, DJ., Guengerich, F.P., Estabrook, R.W., Feyereisen, R., Gonzalez, F.J., Coon, M.J., Gunsalus, I.C., Gotoh, O., Okuda, K., and Nebert, D.W. 1993, The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature, DNA Cell Biol. 12: 1–51.PubMedCrossRefGoogle Scholar
  17. Nguyen, T., Brunson, D., Crespi, C.L., Penman, B.W., Wishnok, J.S., and Tannenbaum, S.R., 1992, DNA damage and mutation in human cells exposed to nitric oxide in vitro, Proc. Natl. Acad. Sci. (USA) 89: 3030–3034.CrossRefGoogle Scholar
  18. Olbregts, J. 1985, Termolecular reaction of nitrogen monoxide and oxygen: A still unsolved problem, Int. J. Chem. Kinet. 17: 835–848.CrossRefGoogle Scholar
  19. Pacelli, R., Krishna, M.C., Wink, D.A., and Mitchell, J.B., 1994, Nitric oxide protects DNA from hydrogen peroxide-induced double strand cleavage, Proc. Am. Assoc. Cancer Res. 35: 540 (abstract 3214).Google Scholar
  20. Routledge, M.N., Wink, D.A., Keefer, L.K., and Dipple, A. 1994, DNA sequence changes induced by two nitric oxide donor drugs in the supF assay, Chem. Res. Toxicol. 7: 628–632.PubMedCrossRefGoogle Scholar
  21. Saffhill. R., Margison, G.P., and O’Connor, P.J. 1985, Mechanisms of carcinogenesis induced by alkylating agents, Biochim. Biophys. Acta 823: 111–145.PubMedGoogle Scholar
  22. Shapiro, H.S., and Chargaff, E. 1966, Studies on the nucleotide arrangement in deoxyribonucleic acids. XI. Selective removal of cytosine as a tool for the study of the nucleotide arrangement in deoxyribonucleic acid, Biochemistry 5: 3012–3018.PubMedCrossRefGoogle Scholar
  23. Stadler, J., Trockfeld, J., Schmalix, W.A., Brill, T., Siewert, J.R., Greim, H., and Doehmer, J. 1994, Inhibition of cytochromes P4501A by nitric oxide, Proc. Natl. Acad. Sci. (USA) 91: 3559–3563.CrossRefGoogle Scholar
  24. Williams, D.L.H., 1988, Nitrosation, Cambridge U. Press, Cambridge.Google Scholar
  25. Wink, D.A., and Laval, J., 1994, The Fpg protein, a DNA repair enzyme, is inhibited by the biomediator nitric oxide in vitro and in vivo, Carcinogenesis 15: 2125–2129.PubMedCrossRefGoogle Scholar
  26. Wink, D.A., Kasprzak, K.S., Maragos, CM., Elespuru, R.K., Misra, M., Dunams, T.M., Cebula, T.A., Koch, W.H., Andrews, A.W., Allen, J.S., and Keefer, L.K. 1991, DNA deaminating ability and genotoxicity of nitric oxide and its progenitors, Science 254: 1001–1003.PubMedCrossRefGoogle Scholar
  27. Wink, D.A., Darbyshire, J.F., Nims, R.W., Saavedra, J.E., and Ford, P.C. 1993a, Reactions of the bioregulatory agent nitric oxide in oxygenated aqueous media: Determination of the kinetics for oxidation and nitrosation by intermediates generated in the NO/O2 reaction, Chem. Res. Toxicol.. 6: 23–27.PubMedCrossRefGoogle Scholar
  28. Wink, D.A., Hanbauer, I., Krishna, M.C, DeGraff, W., Gamson, J., and Mitchell, J.B. 1993b, Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species, Proc. Natl. Acad. Sci. (USA). 90: 9813–9817.CrossRefGoogle Scholar
  29. Wink, D.A., Osawa, Y., Darbyshire, J.F., Jones, C.R., Eshenaur, S.C., and Nims, R.W. 1993c, Inhibition of cytochromes P450 by nitric oxide and a nitric oxide-releasing agent, Arch. Biochem. Biophys.. 300: 115–123.PubMedCrossRefGoogle Scholar
  30. Zimmermann, F.K. 1977, Genetic effects of nitrous acid, Mutat. Res. 39: 127–147.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Larry K. Keefer
    • 1
    • 2
  • David A. Wink
    • 1
    • 2
  1. 1.Chemistry SectionLaboratory of Comparative CarcinogenesisFrederickUSA
  2. 2.National Cancer InstituteFrederick Cancer Research and Development CenterFrederickUSA

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