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• W1982870743 abstract "Although oxygen is a powerful oxidant, the triplet ground state of dioxygen constitutes a kinetic barrier for oxidation of biological molecules, which are mostly singlet state (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar). However, the unpaired orbitals of dioxygen can sequentially accommodate single electrons to yield O·̄2, H2O2, the very reactive ⋅OH, and water (Fig. 1,Reaction 1). The oxidative potential of atmospheric oxygen is maintained by the non-alignment of electron spins, and aerobic life is based upon harnessing energy via the catalytic spin pairing of triplet oxygen by the electron transport chain (2Babcock G.T. Wikström M. Nature. 1992; 356: 301-309Crossref PubMed Scopus (1088) Google Scholar). The latter process occasionally errs, however, giving rise to O·̄2 and other reactive oxygen species (3Imlay J.A. Fridovich I. J. Biol. Chem. 1991; 266: 6957-6965Abstract Full Text PDF PubMed Google Scholar) that cause cellular and genetic damage (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar, 5Lindahl T. Nature. 1993; 362: 709-715Crossref PubMed Scopus (4378) Google Scholar, 6Stadtman E.R. Annu. Rev. Biochem. 1993; 62: 797-821Crossref PubMed Scopus (1270) Google Scholar, 7Dix T.A. Aikens J. Chem. Res. Toxicol. 1993; 6: 2-18Crossref PubMed Scopus (304) Google Scholar). Moreover, catabolic oxidases such as xanthine oxidase, anabolic processes such as nucleoside reduction, and defense processes such as phagocytosis also produce oxygen radicals. Although DNA is a biologically important target for reactive oxygen species, free O·̄2 is relatively unreactive with DNA (8Bielski B.H.J. Cabelli D.E. Aradi R.L. Ross A.B. J. Phys. Chem. Ref. Data. 1985; 14: 1041-1100Crossref Scopus (1864) Google Scholar). However, O·̄2 dismutates (via spontaneous or enzyme-catalyzed reactions) to produce H2O2 (Fig. 1,Reaction 2). O·̄2 can also reduce and liberate Fe3+ from ferritin (9Reif D.W. Free Radical Biol. Med. 1992; 12: 417-427Crossref PubMed Scopus (327) Google Scholar) (Fig. 1, Reaction 3) or liberate Fe2+ from iron-sulfur clusters (10Flint D.H. Tuminello J.F. Emptage M.H. J. Biol. Chem. 1993; 268: 22369-22376Abstract Full Text PDF PubMed Google Scholar) (Fig. 1,Reaction 4); subsequently very reactive oxygen species can form via the Fenton reaction (Fig. 1, Reaction 5). Thus, the cytotoxic effects of O·̄2 (as well as of iron and H2O2) have been linked to DNA damage by way of the Fenton reaction (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar, 11Keyer K. Imlay J.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 13635-13640Crossref PubMed Scopus (695) Google Scholar, 12Mello-Filho A.C. Meneghini R. Mutat. Res. 1991; 251: 109-113Crossref PubMed Scopus (154) Google Scholar) (Fig. 2). Most transition metals have more than one oxidation state besides the ground state, and their valence electrons may be unpaired (13Cotton F.A. Wilkinson G. Advanced Inorganic Chemistry. 5th Ed. John Wiley & Sons, Inc., New York1988: 625-648Google Scholar), allowing one-electron redox reactions. As such, transition metals can react with H2O2 to produce ⋅OH and related oxidants. In 1894, Fenton (14Fenton H.J.H. J. Chem. Soc. ( Lond .). 1894; 65: 899-910Crossref Google Scholar) described the oxidation of tartaric acid by Fe2+ and H2O2, and the stoichiometry of Fe2+ and H2O2consumption was subsequently shown to be consistent with that of Reaction 5 (15Haber F. Weiss J. Proc. R. Soc. Lond. Ser. A Biol. Sci. 1934; 147: 332-351Google Scholar). This review will focus on the iron-mediated Fenton reactions; those with other transition state metals are discussed elsewhere (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar, 16Goldstein S. Meyerstein D. Czapski G. Free Radical Biol. Med. 1993; 15: 435-445Crossref PubMed Scopus (586) Google Scholar). Iron has five oxidation states in aqueous solution, Fe(II)–Fe(VI). Fe(II) and Fe(III) are the most common, and their reactions with oxygen and its reduced forms are well documented (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar, 17Walling C. Acc. Chem. Res. 1975; 8: 125-131Crossref Scopus (2788) Google Scholar). More recently, however, reactions with Fe(IV) have been implicated in biological processes and proposed to be involved in damage to cellular components (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar, 16Goldstein S. Meyerstein D. Czapski G. Free Radical Biol. Med. 1993; 15: 435-445Crossref PubMed Scopus (586) Google Scholar, 18Yamazaki I. Piette L.H. J. Am. Chem. Soc. 1991; 113: 7588-7593Crossref Scopus (254) Google Scholar, 19Wink D.A. Nims R.W. Saavedra J.E. Utermahlen Jr., W.E. Ford P.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6604-6608Crossref PubMed Scopus (143) Google Scholar, 20Wardman P. Candeias L.P. Radiat. Res. 1996; 145: 523-531Crossref PubMed Scopus (482) Google Scholar). For example, in the case of Fe2+ chelates with ADP, ortho-phosphate, or EDTA, the oxidant formed from H2O2 behaves differently than expected for⋅OH, and it has been proposed to be the ferryl radical (Fig. 1,Reaction 6). Alternately, a caged or bound ⋅OH, often denoted as [Fe-H2O2]2+ or [FeOOH]+, might account for the noted differences (18Yamazaki I. Piette L.H. J. Am. Chem. Soc. 1991; 113: 7588-7593Crossref Scopus (254) Google Scholar). This distinction might be arbitrary, however, as this bound ⋅OH might be an intermediate of Reactions 5 or 6 (16Goldstein S. Meyerstein D. Czapski G. Free Radical Biol. Med. 1993; 15: 435-445Crossref PubMed Scopus (586) Google Scholar) and the ferryl radical itself could give rise to ⋅OH via Reaction 7 (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar,18Yamazaki I. Piette L.H. J. Am. Chem. Soc. 1991; 113: 7588-7593Crossref Scopus (254) Google Scholar). Both Fe2+ and Fe3+ may have open orbitals that can share outer sphere electrons with ligands for iron coordination. The chemical properties of such complexes are determined by the ligands (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar, 16Goldstein S. Meyerstein D. Czapski G. Free Radical Biol. Med. 1993; 15: 435-445Crossref PubMed Scopus (586) Google Scholar, 18Yamazaki I. Piette L.H. J. Am. Chem. Soc. 1991; 113: 7588-7593Crossref Scopus (254) Google Scholar). For example, Luo et al. (21Luo Y.-Z. Han Z.-X. Chin S.M. Linn S. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 12438-12442Crossref PubMed Scopus (130) Google Scholar) found that in the presence of the very complex ligand, DNA, there are three kinetically distinguishable oxidants formed that cause DNA strand breakage. One of these is easily scavengable, consistent with it being a freely diffusible ⋅OH, whereas the other two vary in their scavenging susceptibilities, and one or both of these might be an iron(IV) species. Therefore, after 100 years, the basic nature of the Fenton oxidant(s) is still undefined so that “⋅OH” may be regarded as a symbol representing the stoichiometric equivalent of the univalent oxidation agents produced by the Fenton reaction. However, it is clear that whatever the oxidant, hydroxylations and hydrogen abstractions are the two most common modifications of organic substrates by Fenton oxidants (17Walling C. Acc. Chem. Res. 1975; 8: 125-131Crossref Scopus (2788) Google Scholar, 22Henle E.S. Luo Y. Gassman W. Linn S. J. Biol. Chem. 1996; 271: 21177-21186Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 23Luo Y. Henle E.S. Linn S. J. Biol. Chem. 1996; 271: 21167-21176Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). It is noteworthy that H2O2 can also react with Fe3+ to form O·̄2, presumably via Reaction 8 (24Gutteridge J.M. Bannister J.W. Biochem. J. 1986; 234: 225-228Crossref PubMed Scopus (55) Google Scholar), and that if H2O2 is in excess, the Fe2+ which is thus formed can subsequently generate reactive oxygen species via the Fenton reaction. H2O2 and O·̄2 may participate in the production of singlet oxygen and peroxynitrite. The generation of these species may be concurrent with reactions involving iron, and under some circumstances they might be important contributors to H2O2 toxicity (25Sies H. Mutat. Res. 1993; 299: 183-191Crossref PubMed Scopus (91) Google Scholar, 26Squadrito G.L. Pryor W.A. Chem. Biol. Interact. 1995; 96: 203-206Crossref PubMed Scopus (181) Google Scholar). Singlet dioxygen is not spin-restricted from oxidizing organic compounds as is triplet state oxygen (1Koppenol W.H. Rice-Evans C.A. Burdon R.H. Free Radical Damage and Its Control. Elsevier Science Publishing Co., Inc., New York1994: 3-24Google Scholar) and was once proposed to be the product of dioxygen-producing reactions involving either H2O2 or O·̄2 (27Krinsky N.I. Trends Biochem. Sci. 1977; 2: 35-38Abstract Full Text PDF Scopus (125) Google Scholar). However, it now appears that singlet oxygen is not generated via Fenton/Haber-Weiss chemistry. Instead, for example, OCl− produced by the reaction of Cl− with H2O2 (Fig. 1,Reaction 9) might react with H2O2 to generate singlet oxygen (Fig. 1, Reaction 10). Reaction 9 is facilitated by chloroperoxidases, which generate singlet oxygen from H2O2 and chloride in vitro (28Khan A.U. Gebauer P. Hager L.P. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 5195-5197Crossref PubMed Google Scholar), and singlet oxygen is produced in neutrophils, which contain abundant H2O2 and chloroperoxidases (29Steinbeck M.J. Khan A.U. Karnovsky M.J. J. Biol. Chem. 1992; 267: 13425-13433Abstract Full Text PDF PubMed Google Scholar). 1At low pH, HOCl can oxidize O·̄2 or Fe2+ to form a strong oxidant, presumably ⋅OH (20Wardman P. Candeias L.P. Radiat. Res. 1996; 145: 523-531Crossref PubMed Scopus (482) Google Scholar). O·̄2 reacts rapidly with nitric oxide (Fig. 1, Reaction 11) to form peroxynitrite anion (26Squadrito G.L. Pryor W.A. Chem. Biol. Interact. 1995; 96: 203-206Crossref PubMed Scopus (181) Google Scholar) (Reaction 11), the protonated form of which, peroxynitrous acid (pK a = 6.7), reacts well with biological molecules. Alternatively, ONOO− might form singlet oxygen from H2O2 (30Di Mascio P. Bechara E.J. Medeiros M.H. Briviba K. Sies H. FEBS Lett. 1994; 355: 287-289Crossref PubMed Scopus (139) Google Scholar). Consequently, NO⋅ production by nitric oxide synthase may render cells vulnerable to superoxide-mediated damage (31White C.R. Brock T.A. Chang L.Y. Crapo J. Briscoe P. Ku D. Bradley W.A. Gianturco S.H. Core J. Freeman B.A. Tarpey M.M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 1044-1048Crossref PubMed Scopus (662) Google Scholar). A substantial portion of H2O2 lethality involves DNA damage by oxidants generated from iron-mediated Fenton reactions (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar, 12Mello-Filho A.C. Meneghini R. Mutat. Res. 1991; 251: 109-113Crossref PubMed Scopus (154) Google Scholar). It would appear that NADH can drive the process by replenishing Fe2+ from Fe3+ in bacteria andin vitro (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar). Moreover, NADH enhances iron-DNA association (32Luo, Y. (1993) Characterization of Fenton Oxidants and DNA Damage. Ph.D. thesis, University of California, Berkeley.Google Scholar). A large portion of H2O2-dependent DNA damage appears not to be due to diffusible hydroxyl radicals (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar,21Luo Y.-Z. Han Z.-X. Chin S.M. Linn S. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 12438-12442Crossref PubMed Scopus (130) Google Scholar, 33Mello-Filho A.C. Meneghini R. Biochim. Biophys. Acta. 1984; 781: 56-63Crossref PubMed Scopus (305) Google Scholar). Instead, DNA-damaging Fenton oxidants are produced on Fe2+ atoms associated with DNA, and it would appear that the location of iron binding may determine the substrate and nature of attack. There appear to be at least two distinguishable classes of iron-mediated Fenton oxidants of DNA (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar, 21Luo Y.-Z. Han Z.-X. Chin S.M. Linn S. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 12438-12442Crossref PubMed Scopus (130) Google Scholar). Type I oxidants are moderately sensitive to H2O2 and ethanol and appear to cleave DNA preferentially within the sequences R T GR, TA T TY, and CT T R (the bold, underscored nucleotides are the sites of cleavage); Type II oxidants, on the other hand, make preferential cleavages in the sequence NGG G. 2Z. X. Han, M. S. Falk, E. S. Henle, Y. Luo, and S. Linn, unpublished observations. The distinguishing characteristics of these radicals may be predominantly due to localization of the iron that gives rise to them. However, it may be that the sites of nicking are not necessarily the iron-binding sites. The NGGG sites in particular may be sinks for radical electrons, which are formed elsewhere on the helix and travel through the base stack (34Hall D.B. Holmlin R.E. Barton J.K. Nature. 1996; 382: 731-735Crossref PubMed Scopus (864) Google Scholar). Whether there are differences in the spectrum of base damages by the two types of oxidants has not been reported. Damage by Fenton oxidants may occur at the DNA bases or sugars. Sugar damage is initiated by hydrogen abstraction from one of the deoxyribose carbons, and the predominant consequence is eventual strand breakage and base release (35von Sonntag C. The Chemical Basis of Radiation Biology. Taylor and Francis, New York1987: 238-249Google Scholar, 36Henle E.S. Roots R. Holley W.R. Chatterjee A. Radiat. Res. 1995; 143: 144-150Crossref PubMed Scopus (46) Google Scholar). In approximately half of these alterations, a 5′-phosphate end group is located 3′ to the cleavage, a 3′-phosphoglycolate is located 5′ to the cleavage, and a base propenal is released, which subsequently decomposes to the free base and malondialdehyde (37Janicek M.R. Haseltine W.A. Henner W.D. Nucleic Acids Res. 1985; 13: 9011-9029Crossref PubMed Scopus (40) Google Scholar, 38Bertoncini C.R. Meneghini R. Nucleic Acids Res. 1995; 15: 2995-3002Crossref Scopus (72) Google Scholar). The majority of other sugar damages yield 5′- and 3′-phosphomonoesters flanking a one-nucleoside gap. Some sugar alterations, such as the γ-lactone, do not give this product immediately but do so after adequate time or treatment (35von Sonntag C. The Chemical Basis of Radiation Biology. Taylor and Francis, New York1987: 238-249Google Scholar). Another alteration at the sugar moiety is a β to α inversion at the 1′-carbon, which disrupts the B-DNA structure (39Ide H. Yamaoka T. Kimura Y. Biochemistry. 1994; 33: 7127-7133Crossref PubMed Scopus (32) Google Scholar). Simultaneous alteration of a sugar and base moiety of a DNA nucleoside to yield 5′-8-cyclodeoxyribopurines has been reported after ionizing radiation (40Dirksen M.L. Blakely W.F. Holwitt E. Dizdaroglu M. Int. J. Radiat. Biol. 1988; 54: 195-204Crossref PubMed Scopus (75) Google Scholar), and 5′-8-cyclodeoxyguanosine was observed as a product of dGMP subjected to Fe2+ and H2O2, although it has not been shown to occur for H2O2-mediated damage of DNA (22Henle E.S. Luo Y. Gassman W. Linn S. J. Biol. Chem. 1996; 271: 21177-21186Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Radical attack on the bases results primarily in OH addition to the electron-rich double bonds, particularly the purine N-7–C-8 bond and the pyrimidine 5,6 bond (22Henle E.S. Luo Y. Gassman W. Linn S. J. Biol. Chem. 1996; 271: 21177-21186Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 23Luo Y. Henle E.S. Linn S. J. Biol. Chem. 1996; 271: 21167-21176Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar).3 Hydrogen abstraction from thymine-methyl groups also occurs (35von Sonntag C. The Chemical Basis of Radiation Biology. Taylor and Francis, New York1987: 238-249Google Scholar). 3R. Chattopadhyaya, R. Jin, Y. Luo, E. S. Henle, and S. Linn, unpublished observations.In general, radical attack on the base moieties of DNA does not give rise to altered sugars or strand breaks except when base modifications labilize the N-glycosyl bond, allowing the formation of baseless sites that are subject to β-elimination (41Suzuki T. Ohsumi S. Makino K. Nucleic Acids Res. 1994; 22: 4997-5003Crossref PubMed Scopus (109) Google Scholar). Attack at the DNA bases leads to as many as 50 base alterations (22Henle E.S. Luo Y. Gassman W. Linn S. J. Biol. Chem. 1996; 271: 21177-21186Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 23Luo Y. Henle E.S. Linn S. J. Biol. Chem. 1996; 271: 21167-21176Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar,42Mouret J.F. Polverelli M. Sarrazini F. Cadet J. Chem. Biol. Interact. 1991; 77: 187-201Crossref PubMed Scopus (30) Google Scholar, 43Dizdaroglu M. Mutat. Res. 1992; 275: 331-342Crossref PubMed Scopus (499) Google Scholar, 44Jaruga P. Dizdaroglu M. Nucleic Acids Res. 1996; 24: 1389-1394Crossref PubMed Scopus (242) Google Scholar).3 The spectrum of damages due to iron/H2O2 is quite similar to (but is not congruent with) that caused by ionizing radiation (22Henle E.S. Luo Y. Gassman W. Linn S. J. Biol. Chem. 1996; 271: 21177-21186Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,23Luo Y. Henle E.S. Linn S. J. Biol. Chem. 1996; 271: 21167-21176Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar).3 One source of the difference between products formed by Fenton oxidantsversus ionizing radiation could be the participation of iron ions directly in product formation. DNA-bound iron may interact with nascent DNA radicals and thereby qualitatively and quantitatively alter the products (45Henle E.S. Luo Y. Linn S. Biochemistry. 1996; 35: 12212-12219Crossref PubMed Scopus (61) Google Scholar). In the absence of O2, Fe3+can react with reducing DNA radicals (Fig. 1, Reaction 12). In the presence of O2, DNA peroxyl radicals are formed, which can react with Fe2+ (Fig. 1, Reactions 13and 14). These reactions affect the product spectrum and thereby obfuscate identification of the initial oxidants through product analyses. Among the oxidized purines, formamidopyrimidines and 7,8-dihydro-8-oxoguanine (8-oxo-Gua) 4The abbreviations used are: 8-oxo-Gua, 7,8-dihydro-8-oxoguanine; SOD, superoxide dismutase; AP, apurinic/apyrimidinic; drPase, DNA deoxyribosephosphodiesterase. have received widespread study, whereas among the pyrimidines, thymine glycol and its spontaneous hydrolysis products have been actively studied, most likely because of the ubiquitous presence of enzymes for the excision of all of these products (see below). 8-oxo-Gua is also the object of much study because of its highly mutagenic nature (it base pairs relatively well with adenine) (46Michaels M.L. Tchou J. Grollman A.P. Miller J.H. Biochemistry. 1992; 31: 10964-10968Crossref PubMed Scopus (301) Google Scholar) and the relative ease of its isolation and quantitation. Another type of DNA damage mediated by iron in vivo is DNA-protein cross-links, e.g. thymine-tyrosine (47Altman S.A. Zastawny T.H. Randers-Eichhorn L. Cacciuttolo M.A. Akman S.A. Dizdaroglu M. Rao G. Free Radical Biol. Med. 1995; 19: 897-902Crossref PubMed Scopus (84) Google Scholar). DNA interstrand cross-links have not been shown to be formed by oxygen radicals. The fidelity of the metabolic redox reactions (2Babcock G.T. Wikström M. Nature. 1992; 356: 301-309Crossref PubMed Scopus (1088) Google Scholar) and the sequestering of iron in ferritin and transferrin (9Reif D.W. Free Radical Biol. Med. 1992; 12: 417-427Crossref PubMed Scopus (327) Google Scholar, 48Theil E.C. Annu. Rev. Biochem. 1987; 56: 289-315Crossref PubMed Scopus (1124) Google Scholar) generally minimize the burden from reactive oxygen species. Moreover, compartmentalization of free iron and superoxide and the impediment for iron binding to DNA by histones (49Enright H.U. Miller W.J. Hebbel R.P. Nucleic Acids Res. 1992; 20: 3341-3346Crossref PubMed Scopus (83) Google Scholar) diminish the occurrence of Fenton reactions on DNA. Active oxygen species produced by iron/H2O2 are also removed by superoxide dismutases (SODs) (Reaction 1), catalases (Fig. 1, Reaction 15), and peroxidases that catalyze the reduction of H2O2 by organic reductants (RH) such as glutathione, ascorbate, and cytochrome c (Fig. 1,Reaction 16). The major source of protection would appear to be SOD. Mammalian cells produce a mitochondrial Mn-SOD, a cytoplasmic Cu,Zn-SOD that is also found in peroxysomes (50Singh A.K. Dhaunsi G.S. Gupta M.P. Orak J.K. Asayama K. Singh I. Arch. Biochem. Biophys. 1994; 315: 331-338Crossref PubMed Scopus (44) Google Scholar), and an extracellular Cu,Zn-SOD (51Fridovich I. Annu. Rev. Biochem. 1995; 64: 97-112Crossref PubMed Scopus (2755) Google Scholar). Fe-SOD is additionally found in some bacteria and in chloroplasts (52Michiels C. Raes M. Toussaint O. Remacle J. Free Radical Biol. Med. 1994; 17: 235-248Crossref PubMed Scopus (1044) Google Scholar). Since superoxide dismutation forms H2O2, the detoxifying effect of SOD is most likely a result of preventing the accumulation of free Fe2+(Reactions 2 and 3) and peroxynitrite production (Reaction 11). Catalase does not appear to be nearly so important as SOD, judging from the weak phenotypes of cells that lack it (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar) and persons with acatalasemia (53Eaton J.W. Ma M. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 7th Ed. McGraw-Hill, Inc., New York1995: 2371-2383Google Scholar). In mammalian cells catalase is largely contained in peroxysomes (54Amstad P. Peskin A. Shah G. Mirault M.-E. Moret R. Zbinden I. Cerutti P. Biochemistry. 1991; 30: 9305-9313Crossref PubMed Scopus (266) Google Scholar) and to a lesser extent it is secreted (55Sandstrom P.A. Buttke T.M. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4708-4712Crossref PubMed Scopus (188) Google Scholar).Escherichia coli contains two catalases, one regulated by stationary phase and the other by H2O2 exposure (56Heimberger A. Eisenstark A. Biochem. Biophys. Res. Commun. 1988; 154: 392-397Crossref PubMed Scopus (23) Google Scholar). In eukaryotes, glutathione peroxidases are found in the mitochondria, cytoplasm, and peroxysomes (50Singh A.K. Dhaunsi G.S. Gupta M.P. Orak J.K. Asayama K. Singh I. Arch. Biochem. Biophys. 1994; 315: 331-338Crossref PubMed Scopus (44) Google Scholar). These enzymes, especially the selenium glutathione peroxidase, are more effective in removing H2O2 than catalase (52Michiels C. Raes M. Toussaint O. Remacle J. Free Radical Biol. Med. 1994; 17: 235-248Crossref PubMed Scopus (1044) Google Scholar). Peroxidases are less specific than catalase and can also reduce organic hydroperoxides that can react in Fenton-like reactions. Oxidized glutathione is reduced by NADPH-dependent glutathione reductase, an auxiliary enzyme for this antioxidant function. The relative levels of SOD, catalase, and glutathione peroxidase are important. For instance, an increase in SOD would deplete the cell of superoxide but would increase H2O2 production, which might be deleterious unless sufficient catalase and/or glutathione peroxidase were available. Likewise, excess glutathione peroxidase could unnecessarily deplete glutathione and/or NADPH reserves even though sufficient catalase was present (52Michiels C. Raes M. Toussaint O. Remacle J. Free Radical Biol. Med. 1994; 17: 235-248Crossref PubMed Scopus (1044) Google Scholar, 57Cerutti, P., Ghosh, R., Oya, Y., and Amstad, P. (1994) Environ. Health Perspect. , 102, Suppl. 10, 123–129.Google Scholar). Eukaryotes also contain a thiol-specific antioxidant enzyme that acts as a thiol-dependent peroxidase, at least at low H2O2 concentrations (∼50 μm) (58Netto L.E.S. Chae H.Z. Kang S.-W. Rhee S.G. Stadtman E.R. J. Biol. Chem. 1996; 271: 15315-15321Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). At high concentrations of H2O2 (∼10 mm), thiol-specific antioxidant enzyme is reported to protect DNA against damage by thiol/metal-catalyzed oxidation (59Lim Y.S. Cha M.K. Kim H.K. Uhm T.B. Park J.W. Kim K. Kim I.H. Biochem. Biophys. Res. Commun. 1993; 192: 273-280Crossref PubMed Scopus (182) Google Scholar); however, this protection does not appear to be mediated by the peroxidase activity. The only effective means of detoxification of ⋅OH is to scavenge it non-enzymatically. Histones and the compact structure of chromatin protect the DNA by this means (60Milligan J.R. Aguilera J.A. Ward J.F. Radiat. Res. 1993; 133: 158-162Crossref PubMed Scopus (42) Google Scholar). As yet, an enzymatic apparatus for singlet oxygen removal has not been detected; rather the cell appears to employ scavengers such as carotenoids (61Sies H. Stahl W. Am. J. Clin. Nutr. 1995; 62: 1315-1321Crossref PubMed Google Scholar). Raising NADH levels exacerbates H2O2 toxicity in E. coli (4Imlay J.A. Linn S. Science. 1988; 240: 1302-1309Crossref PubMed Scopus (1670) Google Scholar), and NADH increases iron/H2O2-mediated DNA damage in vitro (22Henle E.S. Luo Y. Gassman W. Linn S. J. Biol. Chem. 1996; 271: 21177-21186Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 23Luo Y. Henle E.S. Linn S. J. Biol. Chem. 1996; 271: 21167-21176Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). However, NADPH is at least an order of magnitude slower in reducing Fe3+ and competes very effectively with NADH for iron binding (32Luo, Y. (1993) Characterization of Fenton Oxidants and DNA Damage. Ph.D. thesis, University of California, Berkeley.Google Scholar). It may therefore be important that inE. coli an O·̄2 challenge induces glucose-6-phosphate dehydrogenase and hence raises NADPH levels (62Greenberg J.T. Demple B. J. Bacteriol. 1989; 171: 3933-3939Crossref PubMed Scopus (176) Google Scholar) and that a H2O2 challenge increases the ratio of NADPH to NADH. 5Y. Li and S. Linn, unpublished observations. Moreover, in mammalian cells DNA strand breaks result in the depletion of nuclear NAD+ (and NADH) by forming poly(ADP)-ribose (63Lindahl T. Satoh M.S. Poirer G.G. Klungland A. Trends Biochem. Sci. 1995; 20: 405-411Abstract Full Text PDF PubMed Scopus (578) Google Scholar). Finally, E. coliaconitase is inactivated by superoxide (64Gardener P.R. Fridovich I. J. Biol. Chem. 1991; 266: 19328-19333Abstract Full Text PDF PubMed Google Scholar), thus shutting down the Krebs cycle and NADH production. Direct enzymatic reversion of any oxidative DNA damage product has not been described. However, under some conditions, carbon-centered radicals formed on the DNA backbone by⋅OH attack may be restituted to undamaged DNA by hydrogen donation from a sulfhydryl (65Lafleur M.V.M. Retel J. Mutat. Res. 1993; 295: 1-10Crossref PubMed Scopus (33) Google Scholar). O2, H2O2, and iron may interfere in this “chemical restitution,” and sulfhydryls may in fact exacerbate DNA damage by iron/H2O2 (66Held K.D. Sylvester F.C. Hopcia K.L. Biaglow J.E. Radiat. Res. 1996; 145: 542-553Crossref PubMed Scopus (107) Google Scholar). Once DNA nucleoside damage is manifested, enzymatic mechanisms are necessary to correct the alteration. The damage must be recognized, removed, and replaced with normal nucleotides, and DNA ligase must seal all strand breaks (67Demple B. Harrison L. Annu. Rev. Biochem. 1994; 63: 915-948Crossref PubMed Scopus (1300) Google Scholar). Base excision repair is manifested through a DNA glycosylase, which recognizes the damaged base and cleaves its glycosylic bond (68Dodson M.L. Michaels M.L. Lloyd R.S. J. Biol. Chem. 1994; 269: 32709-32712Abstract Full Text PDF PubMed Google Scholar, 69Sancar A. Annu. Rev. Biochem. 1996; 65: 43-81Crossref PubMed Scopus (965) Google Scholar). An enzyme recognizing hydroxymethyluracil is present in eukaryotes (70Cannon-Carlson S.V. Gokhale H. Teebor G.W. J. Biol. Chem. 1989; 264: 13306-13312Abstract Full Text PDF PubMed Google Scholar) but apparently not in bacteria (71Lloyd R.S. Linn S. Linn S. Lloyd R.S. Roberts R.J. Nucleases. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1993: 263-316Google Scholar). Its role would appear to be to avoid mutations due to the formation of hydroxymethyluracil upon oxidation of 5-methylcytosine in DNA. Most organisms appear to contain formamidopyrimidine (FAPy) glycosylases (Fpg protein) and several pyrimidine hydrate DNA glycosylases (e.g. E. coli endonucleases III and VIII). The former recognizes formamidopyrimidines and 8-oxopurines. The latter recognizes thymine glycols, pyrimidine hydrates, and their degradation products. Saccharomyces cerevisiae is exceptional in having an enzyme that recognizes both pyrimidine hydrates and formamidopyrimidines but not 8-oxo-Gua (72Eide L. Bjorås M. Pirovano M. Alseth I. Berdal K.G. Seeberg E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10735-10740Crossref PubMed Scopus (146) Google Scholar). These enzymes also catalyze a β-lyase activity that cleaves a 3′-phosphodiester of a baseless sugar (AP site), leaving a nick with an unsaturated sugar at the 3′ terminus and a 5′-phosphomonoester group (Fig. 1, Reaction 17). The function, if any, of the β-lyase activities is unknown. In addition, DNA deoxyribosephosphodiesterase (drPase) activities exist that utilize hydrolytic mechanisms for removing 5′ or 3′ sugar residues or sugar fragments such as glycolyate residues. Moreover, ubiquitous class II AP endonucleases initiate sugar removal by hydrolyzing the 5′-phosphodiester bond of an AP site (Fig. 1, Reaction 18). The resulting 5′-terminal deoxyribose phosphate is a substrate for the drPase or β-lyase activity of the DNA glycosylases. Once the baseless sugars or sugar fragments are removed, the small gap is filled, most likely by DNA polymerase I in bacteria or DNA polymerase β in higher eukaryotes and then sealed by DNA ligase. A mismatch repair DNA glycosylase in E. coli (MutY) (46Michaels M.L. Tchou J. Grollman A.P. Miller J.H. Biochemistry. 1992; 31: 10964-10968Crossref PubMed Scopus (301) Google Scholar) and in human cells (73McGoldrick J.P. Yeh Y.C. Solomin M. Essigmann J.M. Lu A.L. Mol. Cell. Biol. 1995; 15: 989-996Crossref PubMed Google Scholar) is an adenine DNA glycosylase that removes adenine when it is paired to 8-oxo-Gua. After the adenine is replaced by cytosine, the 8-oxo-Gua is then excised by the Fpg protein, which does not act on 8-oxo-Gua:A mismatches. This process is catalyzed by large enzyme complexes that ultimately result in the excision of an oligonucleotide of roughly 13 nucleotides in procaryotes or 28 nucleotides in eukaryotes (69Sancar A. Annu. Rev. Biochem. 1996; 65: 43-81Crossref PubMed Scopus (965) Google Scholar). Undoubtedly a subset of oxidative damage is removed by this pathway. A unique pathway for repair of 8-oxo-Gua lesions has been reported in human cell extracts in which an 8-oxo-Gua endonuclease recognizes the lesion and makes incisions immediately 3′ and 5′ to it to form a 1-nucleotide gap (74Bessho T. Tano K. Kasai H. Ohtsuka E. Nishimura S. J. Biol. Chem. 1993; 268: 19416-19421Abstract Full Text PDF PubMed Google Scholar). Exonucleases also take part in nucleotide excision repair in the capacity of nick translation, removal of unpaired damaged termini, or in the removal of abnormal 3′ termini such as phosphomonoesters or phosphoglycolates (75Kornberg A. Baker T.A. DNA Replication. 2nd Ed. W. H. Freeman and Co., New York1992: 142-144Google Scholar, 76Mosbaugh D.W. Linn S. J. Biol. Chem. 1983; 258: 108-118Abstract Full Text PDF PubMed Google Scholar). Double strand breaks and DNA-protein cross-links formed by oxygen radicals are repaired either by homologous recombination or by non-homologous end joining. In homologous recombination, double strand breaks are initially processed by degrading the 5′-ends to reveal 3′-OH single strand overhangs. These single strands associate with undamaged homologous DNA, which acts as a scaffold and template for resynthesis of the 5′-degraded ends from the 3′-OH overhangs (77Shinohara A. Ogawa T. Trends Biochem. Sci. 1995; 20: 387-391Abstract Full Text PDF PubMed Scopus (3) Google Scholar). In mammalian cells, double strand breaks are predominantly repaired by non-homologous end joining (illegitimate recombination), and it seems that this mode of repair is mediated by the V(D)J system, which rejoins blunt double strand breaks (78Jackson S.P. Jeggo P.A. Trends Biochem. Sci. 1995; 20: 412-415Abstract Full Text PDF PubMed Scopus (343) Google Scholar). Since homologous DNA does not act as a scaffold, nucleotides may be lost and ends from different molecules may be joined resulting in gross chromosomal rearrangements. By being mutagenic, reactive oxygen species have been implicated in cancer and other degenerative diseases. However, p53-dependent apoptosis seems to be mediated by reactive oxygen species (79Johnson T.M. Yu Z.-X. Ferrans V.J. Lowenstein R.A. Finkel T. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 11848-11852Crossref PubMed Scopus (525) Google Scholar), so these agents have diametrical effects; they cause undesirable cellular alterations but also prevent undesirable consequences of DNA damage by helping to eliminate damaged cells. A final consideration is DNA damage to mitochondrial DNA. Clearly mitochondrial DNA is damaged by reactive oxygen species, and pyrimidine hydrate DNA glycosylases (80Tomkinson A.E. Bonk R.T. Kim J. Bartfeld N. Linn S. Nucleic Acids Res. 1990; 18: 929-935Crossref PubMed Scopus (72) Google Scholar), AP endonuclease (81Tomkinson A.E. Bonk T. Linn S. J. Biol. Chem. 1988; 263: 12532-12537Abstract Full Text PDF PubMed Google Scholar), and a recombination (82Thyagurajun B. Padua R.A. Campbell C. J. Biol. Chem. 1996; 271: 27536-27543Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar) exist in mitochondria. Whether repair of the multiple mitochondrial genomes of the cell is sufficient to prevent an accumulation of ineffective mitochondrial genomes and hence an age-related “error-catastrophe” is an active area of interest." @default.
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• W1982870743 date "1997-08-01" @default.
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• W1982870743 title "Formation, Prevention, and Repair of DNA Damage by Iron/Hydrogen Peroxide" @default.
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