Oxidative damage of DNA caused by a variety of chemical and physical agents appears to be linked to cancer. However, it is becoming increasingly clear that endogenous generation of oxidants, such as hydroxyl radical and peroxynitrite, lead to oxidation of DNA, and this may cause cancer in individuals where no obvious exposure to chemical or physical agents known to be carcinogenic has occurred. The mechanisms for generation of these two oxidants in living organisms will be discussed and their reactivities with DNA to produce oxidized products (e.g., 8-oxo-dG) will be presented with special emphasis on the individual characteristics of the generation and reactivity of each oxidant.
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References
1.
FloydRA. The role of 8-hydroxyguanine in carcinogenesis. Carcinogenesis11: 1447–1450, 1990.
2.
KasaiH, CrainPF, KuchinoY, NishimuraS, OotsuyamaA, TanookaH.Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis7: 1849–1851, 1986.
3.
KasaiH, NishimuraS, KurokawaV, HayashiY.Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. Carcinogenesis8: 1959–1961, 1987.
4.
FailaE, ConwayC, MathisJ.Oxidative DNA and RNA damage in the livers of Sprague-Dawley rats treated with the hepatocarcinogen 2-nitropropane. Cancer Res49: 5518–5522, 1989.
5.
UnemuraT, SaiK, TakagiA, HasegawaR, KurokawaY.Formation of 8-hydroxydeoxyguanosine (8-OHdG) in rat kidney DNA after intraperitoneal administration of ferric nitrilotriacetate (Fe-NTA). Carcinogenesis11: 345–347, 1990.
6.
AcworthIN, BaileyB.The Handbook of Oxidative Metabolism. Chelmsford, MA: ESA, Inc., 1996.
7.
LaufferRB. Iron, aging, and human disease: Historical background and new hypothesis. In: LaufferRB, Ed. Iron and Human Disease. Boca Raton, FL: CRC Press, pp 1–20, 1992.
8.
KinlenU, WillowsAN. Decline in the lung cancer hazard: A prospective study of the mortality of iron ore miners in Cumbria. Br J Ind Med45: 219–224, 1988.
9.
BoydJT, DollR, FauldsJS, LeiperJ.Cancer of the lung in iron ore (haematite) miners. Br J Ind Med27: 97–105, 1970.
10.
AkarasereenontP, MitchellJA, BakhleYS, ThiemermannC, VaneJR. Comparison of the induction of cyclooxygenase and nitric oxide synthase by endotoxin in endothelial cells and macrophages. Eur J Pharmacol273: 121–128, 1995.
11.
BradbearRA, BainC, SiskindV, SchofieldFD, WebbS, AxelsenEM, HallidayJW, BassettML, PowellLW. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst75: 81–84, 1985.
12.
OkudaK.Early recognition of hepatocellular carcinoma. Hepatology6: 1054–1056, 1986.
13.
SalataH, CortesJM, de SalamancaRE. Porphyria cutanea tarda and hepatocellular carcinoma. J Hepatol1: 477–487, 1985.
14.
StevensMG, BeasleyRP, BlumbergBJ. Iron-binding proteins and risk of cancer in Taiwan. J Natl Cancer Inst76: 605–610, 1986.
15.
SelbyJV, FriedmanGD. Epidemiologic evidence of an association between body iron stores and risk of cancer. Int J Cancer41: 677–682, 1988.
16.
StevensRG, JonesDY, MiiozziMS, TaylorPR. Body iron status and the risk of cancer. N Engl J Med319: 1047–1052, 1988.
17.
ReidTM, FeigDI, LoebLA. Mutagenesis by metal-induced oxygen radicals. Environ Health Perspect102: 57–61, 1994.
18.
FeigDI, LoebLA. Mechanisms of mutation by oxidative DNA damage: Reduced fidelity of mammalian DNA polymerase-β. Biochemistry32: 4466–4473, 1993.
19.
ParkS-H, AustAE. Participation of iron and nitric oxide in the mutagenicity of asbestos in hgprf-, gpt+ Chinese hamster V79 cells. Cancer Res58: 1144–1148, 1998.
20.
ChaoC-C, ParkS-H, AustAE. Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells. Arch Biochem Biophys326: 152–157, 1996.
21.
RobertsonFK, LongBW, ToberKL, RossMS, OberyszynTM. Gene expression and cellular sources of inducible nitric oxide synthase during tumor promotion. Carcinogenesis17: 2053–2059, 1996.
22.
AmbsS, MerriamWG, BennettWP, Felley-BoscoE, OgunfusikaMO, OserSM, KleinS, ShieldsPG, BilliarTR, HarrisCC. Frequent nitric oxide synthase-2 expression in human colon adenomas: Implication for tumor angiogenesis and colon cancer progression. Cancer Res58: 334–341, 1998.
23.
YoshieY, OhshimaH.Synergistic induction of DNA strand breakage by catechol-estrogen and nitric oxide: Implications for hormonal carcinogenesis. Free Radic Biol Med24: 341–348, 1998.
24.
MannickEE, BravoLE, ZaramaG, RealpeJL, ZhangXJ, RuizB, FonthamET, MereR, MillerMJ, CorreaP.Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: Effect of antibiotics and antioxidants. Cancer Res56: 3238–3243, 1996.
25.
HarrisCC. Structure and function of the p53 tumor suppressor gene: Clues for rational cancer therapeutic strategies. J Natl Cancer Inst88: 1442–1445, 1996.
26.
KoLJ, PrivesC.p53: Puzzle and paradigm. Genes Dev10: 1054–1072, 1996.
27.
GottliebTM, OrenM.p53 in growth control and neoplasia. Biochim Biophys Acta1287: 77–102, 1996.
28.
HollsteinM, SidranskyD, VogelsteinB, HarrisCC. p53 Mutations in human cancers. Science253: 49–53, 1991.
29.
AmbsSA, HussainSP, HarrisCC. Interactive effects of nitric oxide and the p53 tumor suppressor gene in carcinogenesis and tumor progression. FASEB J11: 443–448, 1997.
30.
HattoriY, NishigoriC, TanakaT, UchidaK, NikaidoO, OsawaT, HiaiH, ImamuraS, ToyokuniS.8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure. J Invest Dermatol107: 733–737, 1996.
31.
SataN, Klonowski-StumpeH, HanB, HaussingerD, NiederauC.Cytotoxicity of peroxynitrite in rat pancreatic acinar AR4-2J cells. Pancreas15: 278–284, 1997.
32.
JuedesMJ, WoganGN. Peroxynitrite-induced mutation spectra of pSP189 following replication in bacteria and in human cells. Mutat Res349: 51–61, 1996.
33.
SalgoMG, StoneK, SquadritoGL, BattistaJR, PryorWA. Peroxynitrite causes DNA nicks in plasmid pBR322. Biochem Biophys Res Commun210: 1025–1030, 1995.
34.
KennedyLJ, MooreKJr.Quantitation of 8-oxoguanine and strand breaks produced by four oxidizing agents. Chem Res Toxicol10: 386–392, 1997.
35.
YermilovV, RubioJ, BecchiM, FriesemM, PignatelliB, OhshimaH.Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. Carcinogenesis16:2045–2050, 1995.
36.
YermilovV, YoshieY, RubioJ, OhshimaH.Effects of carbon dioxide/bicarbonate on induction of DNA single-strand breaks and formation of 8-nitroguanine, 8-oxoguanine, and base-propenal mediated by peroxynitrite. Fed Eur Biochem Sci Lett399: 67–70, 1996.
37.
DoukiT, CadetJ.Peroxynitrite-mediated oxidation of purine bases of nucleosides and isolated DNA. Free Radic Res24: 369–380, 1996.
38.
DoukiT, CadetJ, AmesBN. An adduct between peroxynitrite and 2'-deoxyguanosine. Chem Res Toxicol9: 3–7, 1996.
39.
KuchinoY, MoriF, KasaiH. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature327: 77–79, 1987.
40.
WoodM, DizdarogluM, GajewskiE, EssigmannJ.Mechanistic studies of ionizing radiation and oxidative mutagenesis: Genetic effect of a single 8–hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome. Biochemistry29: 7024–7032, 1990.
41.
MoriyaM, OuC, BodepudiV, JohnsonF, TakeshitaM, GrollmanAP. Site-specific mutagenesis using a gapped duplex vector: A study of translesion synthesis past 8-oxodeoxyguanosine in E. coli. Mutat Res362: 281–288, 1991.
42.
ShibutaniS, TakeshitaM, GrollmanAP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature349: 431–434, 1991.
43.
ChengKC, CahillDS, KasaiH, NishimuraS, LoebLA. 8-Hydroxy-guanine, an abundant form of oxidative DNA damage, causes G → T and A → C substitutions. J Biol Chem267: 166–172, 1992.
44.
BreimerLH. Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis: The role of DNA base damage. Mol Carcinog3: 188–197, 1990.
45.
DizdarogluM, RaoG, HalliwellB, GajewskiE.Damage to the DNA bases in mammalian chromatin by hydrogen peroxide in the presence of ferric and cupric ions. Arch Biochem Biophys285: 317–324, 1991.
46.
von SonntagC. In: GlassWA, VarmaMN, Eds. Molecular Radiation Biology. New York: Plenum Press, pp 287–320, 1991.
47.
FloydR, WatsonJ, WongP, AltmillerD, RickardR.Hydroxyl free radical adduct of deoxyguanosine: Sensitive detection and mechanisms of formation. Free Radic Res1: 163–172, 1986.
48.
TretyakovaNY, NilesJC, BumeyS, WishnokJS, TannenbaumSR. Peroxynitrite-induced reactions of synthetic oligonucleotides containing 8-oxoguanine. Chem Res Toxicol12: 459–466, 1999.
49.
MillerDM, BuettnerGR, AustSD. Transition metals as catalysts of “autoxidation” reactions. Free Radic Biol Med8: 95–108, 1990.
50.
LundLG, AustAE. Iron mobilization from asbestos by chelators and ascorbic acid. Arch Biochem Biophys278: 60–64, 1990.
51.
HalliwellB, GutteridgeJM. Free Radicals in Biology and Medicine. Oxford: Oxford University Press, pp 107–108, 1989.
52.
GrishamMB. Reactive Metabolites of Oxygen and Nitrogen in Biology and Medicine. Georgetown, TX: R.G. Landes Company, pp 47–48, 1992.
HutchinsonF.The distance that a radical formed by ionizing radiation can diffuse in a yeast cell. Radiat Res7: 473–483, 1957.
55.
KissnerR, NauserT, BugnonP, LyePG, KoppenolWH. Formation and properties of peroxynitrite as studied by laser flash photolysis, high-pressure stopped-flow technique, and pulse radiolysis. Chem Res Toxicol10: 1285–1292, 1997.
56.
KoppenolWH. A thermodynamic appraisal of die radical sink hypothesis. Free Radic Biol Med14: 91–94, 1993.
57.
HibbsJBJr.Nitric oxide: A cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun157: 87–94, 1988.
58.
MariettaMA, YoonPS, IyengarR, LeafCD, WishnokJS. Macrophage oxidation of L-arginine to nitrite and nitrate: Nitric oxide is an intermediate. Biochemistry27: 8706–8711, 1988.
59.
BeckmanJS, BeckmanTW, ChenJ, MarshallPA, FreemanBA. Apparent hydroxyl radical production by peroxynitrite. Proc Natl Acad Sci U C A87: 1620–1624, 1990.
60.
KoppenolW, MorenoJ, PryorW, IshiropoulosH, BeckmanJ.Peroxynitrite: A cloaked oxidant from superoxide and nitric oxide. Chem Res Toxicol5: 834–842, 1992.
61.
CrowJP, SpruellC, ChenJ. On the pH-dependent yield of hydroxy radical products from peroxynitrite. Free Radic Biol Med16: 331–338, 1994.
62.
PryorWA, SquadritoGL. The chemistry of peroxynitrite: A product from the reaction of nitric oxide with superoxide. Am J Physiol268: L699–L722, 1995.
BeckmanJS. The Physiological and Pathological Chemistry of Nitric Oxide. San Diego, CA: Academic Press, Inc., pp 1–82, 1996.
68.
MariaSS, LeeJ, GroveJT. Peroxynitrite rapidly permeates phospholipid membranes. Proc Natl Acad Sci U S A94: 14243–14248, 1997.
69.
TsaiJ-HM, HarrisonJG, MartinJC, HamiltonTP, van der WoerdM, JablonskyMJ, BeckmanJS. Role of conformation of peroxynitrite anion (ONOO-) in its stability and toxicity. J Am Chem Soc116: 4115–4116, 1994.
70.
BeckmanJS, IschiropoulosH, ZhuL. Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch Biochem Biophys298: 438–445, 1992.
71.
WhiteR, CrowJ, SpearN, ThomasS, PatelR, GreenI, BeckmanJ, Darley-UsmarV.Making and working with peroxynitrite. In: Tither-adgeMA, Ed. Nitric Oxide Protocols. Totowa, NJ: Humana Press, Vol 100: pp 215–230, 1998.
72.
von SonntagC.The Chemical Basis of Radiation Biology. London: Taylor & Francis, pp 167–193, 1987.
73.
DizdarogluM, Schulte-FrohlindeD, von SonntagC.Strand breaks and sugar release by γ irradiation of DNA in aqueous solution: The effect of oxygen. Zeitshrift fur Naturforschung, Teil C: Biosciences30: 826–828, 1975.
74.
BeeskF, DizdarogluM, Schulte-FrohlindeD, von SonntagC.Radiation-induced strand breaks in deoxygenated aqueous solution: The formation of altered sugars as end groups. Int J Radiat Biol36: 565–576, 1979.
75.
DizdarogluM, Schulte-FrohlindeD, von SonntagC.Isolation of 2–de-oxy-D-erythro-pentonic acid from an alkali-labile site in γ-irradiated DNA. Int J Radiat Biol32: 481–483, 1977.
76.
DizdarogluM, Schulte-FrohlindeD, von SonntagC.γ-Radiolysis of DNA in oxygenated aqueous solution: Structure of an alkali-labile site. Zeitschrift fur Naturforschung, Teil C: Biosciences32: 1021–1022, 1977.
77.
GoldbergIH. Free radical mechanisms in neocarzinostatin-induced DNA damage. Free Radic Biol Med3: 41–54, 1987.
78.
SteenkenS.Addition-elimination paths in electron-transfer reactions between radicals and molecules. J Chem Soc, Faraday Trans183: 113–124, 1987.
79.
O'neillP.Pulse radiolytic study of the interaction of thiols and ascorbate with OH-adducts of dGMP and dG: Implications for DNA repair processes. Radiat Res96: 198–210, 1983.
80.
VieiraAJSC, SteenkenS.Pattern of OH radical reactions with N6,N6-dimethyladenosine: Production of three isomeric OH adducts and their dehydration and ring-opening reactions. J Am Chem Soc109: 7441–7448, 1987.
81.
VieiraAJSC, SteenkenS.Pattern of OH radical reactions with adenine and its necleosides and necleotides: Characterization of two types of isomeric OH adduct and their unimolecular transformation reactions. J Am Chem Soc112: 6986–6994, 1990.
82.
UppuRM, CuetoR, SquadritoGL, SalgoMG, PryorWA. Competitive reactions of peroxynitrite with 2'-deoxyguanosine and 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG): Relevance to the formation of 8-oxodG in DNA exposed to peroxynitrite. Free Radic Biol Med21: 407–411, 1996.
83.
BurneyS, CalufleldJL, NilesJC, WishnokJS, TannenbaumSR. The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res424: 37–49, 1999.
