Nitrogen Dioxide as an Oxidizing Agent of 8-Oxo-7,8-dihydro-2

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Nitrogen Dioxide as an Oxidizing Agent of 8-Oxo-7,8-dihydro-2′-deoxyguanosine but Not of 2′-Deoxyguanosine Vladimir Shafirovich,*,† Jean Cadet,‡ Didier Gasparutto,‡ Alexander Dourandin,† and Nicholas E. Geacintov† Chemistry Department and Radiation and Solid State Laboratory, 31 Washington Place, New York University, New York, New York 10003-5180, and Laboratoire “Le´ sions des Acides Nucle´ iques”, SCIB/DRFMC and UMR CNRS 5046, CEA/Grenoble, 17, rue des Martyrs, F-38054 Grenoble, Cedex 9, France Received September 14, 2000

The redox reactions of guanine and its widely studied oxidation product, the 8-oxo-7,8-dihydro derivative, are of significant importance for understanding the mechanisms of oxidative damage in DNA. Employing 2′-deoxyguanosine 5′-monophospate (dGMP) and 8-oxo-7,8-dihydro-2′deoxyguanosine (8-oxo-dG) in neutral aqueous solutions as model systems, we have used nanosecond laser flash photolysis to demonstrate that neutral radicals, dGMP(-H)•, derived by the one-electron oxidation and deprotonation of dGMP, can oxidize nitrite anions (NO2-) to the nitrogen dioxide radical •NO2. In turn, we show that •NO2 can give rise to a one-electron oxidation of 8-oxo-G, but not of dGMP. The one-electron oxidation of dGMP was initiated by a radical cation generated by the laser pulse-induced photoionization of a pyrene derivative with enhanced water solubility, 7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene (BPT). The dGMP(-H)• neutral radicals formed via deprotonation of the dGMP•+ radical cations and identified by their characteristic transient absorption spectrum (λmax ∼ 310 nm) oxidize nitrite anions with a rate constant of (2.6 ( 0.3) × 106 M-1 s-1. The 8-oxo-dG is oxidized by •NO2 with a rate constant of (5.3 ( 0.5) × 106 M-1 s-1. The 8-oxo-dG(-H)• neutral radicals thus generated are clearly identified by their characteristic transient absorption spectra (λmax ∼ 320 nm). The rate constant of 8-oxo-dG oxidation (k12) by the •NO2 one-electron oxidant (the •NO2/NO2- redox potential, E° ≈ 1.04 V vs NHE) is lower than k12 for a series of oxidizing aromatic radical cations with known redox potentials. The k12 values for 8-oxo-dG oxidation by different aromatic radical cations derived from the photoionization of their parent compounds depend on the redox potentials of the latter, which were in the range of 0.8-1.6 V versus NHE. The magnitude of k12 gradually decreases from a value of 2.2 × 109 M-1 s-1 (E° ) 1.62 V) to 5.8 × 108 M-1 s-1 (E° ) 1.13 V) and eventually to 5 × 107 M-1 s-1 (E° ) 0.91 V). The implications of these results, including the possibility that the redox cycling of the •NO2/NO2- species can be involved in the further oxidative damage of 8-oxo-dG in DNA in cellular environments, are discussed.

Introduction Nitric oxide is generated by vascular endothelial cells to regulate a variety of diverse biochemical and physiological processes, including blood pressure modulation, signal transduction, smooth muscle relaxation, platelet activation, and aggregation (1). Various reactive nitrogen species produced by the reaction of •NO in a cellular environment can induce a variety of DNA lesions, including base modifications that, if not repaired, can give rise to mutations. For example, N2O3 gives rise to nitrosation and subsequent deamination of DNA bases (2, 3), while peroxynitrite induces mostly oxidation and nitration of the nucleic acid bases (4-14). The primary targets of peroxynitrite attack are guanines (12), the most readily oxidized of the four natural DNA bases. A variety of * To whom correspondence should be addressed: Chemistry Department and Radiation and Solid State Laboratory, 31 Washington Place, New York University, New York, NY 10003-5180. Telephone: (212) 998-8456. Fax: (212) 998-8421. E-mail: [email protected]. † New York University. ‡ CEA/Grenoble.

reaction products have been reported with the main components, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG)1 (9, 11) and 8-nitro-2′-deoxyguanosine (8-nitrodG) which is spontaneously released from DNA in the form of 8-nitroguanine (8-nitro-G) by depurination (57, 11). Furthermore, 8-oxo-dG is more reactive with respect to strong oxidants than the parent guanine residues and A, C, and T bases (8, 13-18). These observations are fully consistent with recent computational studies (19, 20). Another reactive nitrogen species that is known to be mutagenic is •NO2 (21-23). This nitrogen dioxide radical can be generated in a cellular environment by the oxidation of nitrite, NO2-, a process that can be mediated by myeloperoxidase (24, 25) as well as by other cellular oxidants (26-28). Nitrite itself is an end product of the reaction of nitric oxide with oxygen (29) and is normally present at concentrations of 1 µs time scales (Figure 4). Thus, photoionization of BPT in the deoxygenated aqueous solutions containing NO3- prevents the formation of O2•- radicals (reaction 3 in Table 1) which can induce undesirable side reactions (e.g., reaction 9 in Table 1). The reaction of •NO2 with 8-oxo-dG was monitored at the maximum of the transient absorbance of 8-oxo-dG radicals at 320 nm (Figure 4). The one-electron oxidation of 8-oxo-dG leads to the radical cation 8-oxo-dG•+ which, at pH 7, is in equilibrium with its deprotonated form, 8-oxo-dG(-H)•, since its pK ) 6.6 (36). Thus, no attempt

(3.4 ( 0.4) × 9.7 × 109 4 × 109 5 × 108 (5 ( 1) × 106 4.5 × 108 6.9 × 103 s-1 1 × 103 s-1

108

ref this work 60 60 60 this work 54 54 54

Figure 4. Kinetics of the transient absorbance at 320 nm induced by 355 nm Nd:YAG laser pulse excitation (60 mJ pulse-1 cm-2) of a deoxygenated 20 mM phosphate buffer solution (pH 7) containing 25 µM BPT, 20 mM NaNO2, 50 mM NaNO3, and various concentrations of 8-oxo-dG. [8-oxo-dG] ) 0.75 (trace 1), 0.50 (trace 2), 0.25 (trace 3), and 0.10 mM (trace 4). The dependence of the initial rate of 8-oxo-dG oxidation by •NO on 8-oxo-dG concentration is shown in the inset. 2

was made to distinguish spectroscopically between these two species. When the transient absorbance due to the formation of 8-oxo-dG•+/8-oxo-dG(-H)• radicals is monitored at 320 nm, three components can be distinguished (Figure 4). The prompt component rises within less than 200 ns and is due to reaction 12, the oxidation of 8-oxo-dG by BPT•+. This amplitude thus increases with increasing 8-oxo-dG concentration. The second component reflects the slower increase in the level of the 8-oxo-dG•+/8-oxo-dG(-H)• radicals which is negligible at low 8-oxo-dG concentrations (e.g., 0.1 mM in Figure 4) and is most pronounced at the highest 8-oxodG concentrations. This component represents the oxidation of 8-oxo-dG by •NO2 according to reaction 16 with the rate constant k16 (Table 3). The initial rates of the reaction (calculated from the experimental kinetic traces in Figure 4 using an 320 of 11.5 × 103 M-1 cm-1; 36) in the ∼1-50 µs range are plotted as a function of the concentration of 8-oxo-dG, and the plot is linear in character. The slope of the straight line is k16[•NO2]0 (≈40 s-1), from which a k14 of (5 ( 1) × 106 M-1 s-1 is calculated ([•NO2]0 at time zero was ∼7.5 µM). The value of k16 is relatively small. Thus, even at the higher concentrations of 8-oxo-dG (Figure 4), the dimerization reaction of •NO2 radicals (reactions 17 in Table 3), followed by the hydrolysis of N2O4 to form stable products (reaction 18 in Table), should be competitive.

Discussion Generation of •NO2 Radicals by One-Electron Oxidation of NO2-. Nitrite is a major end product of NO• metabolism (29), and increased levels of NO2- can serve as markers of enhanced production of •NO in response to the appearance of diverse inflammatory (61)

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and infectious (62) processes. In vivo, NO2- does not accumulate because it is rapidly oxidized by oxyhemoglobin or oxymyoglobin to NO3- (29, 63). However, inflammatory oxidants, such as hypochlorous acid (HOCl) and hydrogen peroxide, can convert NO2- to the highly reactive species NO2Cl and •NO2 via mammalian peroxidase-dependent pathways (24-28, 64). In NO2- oxidation by H2O2, the peroxidases act as one-electron oxidants. Compound I, the primary product of the H2O2 and peroxidase reaction and a potentially two-electron oxidant (65-67), causes one-electron oxidation of NO2- with formation of compound II and •NO2. Compound II oxidizes NO2- with formation of the second •NO2 radical and recovering the initial form of the peroxidase (24, 26). The • NO2 radicals that are formed can nitrate tyrosine in proteins (28, 34, 64); they also participate in the formation of carcinogenic nitrosamines (68, 69), and 8-nitrodG/8-nitro-G (25). Hence, one-electron oxidation of NO2with the formation of •NO2 can be considered a very important pathway of NO2- metabolic activation. The one-electron oxidation of NO2- requires interaction with strong one-electron oxidants with an E° of >1 V versus NHE (58). Kinetic measurements performed in this work show that the rate constant of oxidation of NO2- by BPT•+ (E° ∼ 1.5 V vs NHE) is lower than the rate constant of oxidation of dGMP by BPT•+, although the redox potential E7[G•(-H)/G] of 1.29 V versus NHE (55) is greater than the E°(•NO2/NO2-) of 1.04 V versus NHE (58). The rate constant of NO2- oxidation (2.6 × 106 M-1 s-1) by dGMP•(-H) is also significantly lower than the rate constant of 1,2,4-trimethoxybenzene (E° ) 1.13 V vs NHE) oxidation (6.3 × 108 M-1 s-1) by dG(H)• (55). These results indicate that the reactivities of NO2- in reactions with these one-electron oxidants, either aromatic radical cations or neutral radicals, are lower than expected from differences in redox potentials alone. The detailed analysis of the •NO2/NO2- system published in the recent review (70) of Stanbury suggests that this system is characterized by a small self-exchange rate constant (0.3 M-1 s-1) and a high internal reorganization energy (129 kJ/mol) that results in a low reactivity of NO2- in bimolecular outer sphere electron transfer reactions. Oxidized guanine residues are important intermediates in alkali-mediated DNA strand cleavage reactions (44) and are generated by the reactions of DNA with •OH radicals, or strong oxidants and ionizing radiation (4143). In neutral aqueous solutions, the radical cations dG•+ deprotonate on sub-microsecond time scales to form the neutral radical dG(-H)• (38). While Steenken (42) has suggested that in DNA this deprotonation occurs even more rapidly than in the case of dG in aqueous solution, this has not been demonstrated directly. The decay pathways of the guanine radicals in DNA are complex and can include a variety of bimolecular reactions (43, 71). The reaction of G(-H)• with O2 is slow (k < 106 M-1 s-1; 43). The hydration of G(-H)•, proposed as an important step in the formation of 8-oxo-dG in doublestranded DNA (72), occurs with an even lower rate constant (k < 0.1 s-1; 43). Another possible reaction pathway of the G(-H)• decay is its reaction with O2•radicals (reaction 6). The value of the rate constant k6 (1.3 × 109 M-1 s-1), calculated here on the assumption that O2•- forms with the same yield as dGMP•(-H) and reacts solely with dGMP(-H)•, is close to the value (∼3 × 109 M-1 s-1) recently estimated by Candeias and

Shafirovich et al.

Steenken (43). However, even in the absence of oxygen reactive species (O2 and O2•-), the dG(-H)• or dGMP(H)• radicals are unstable and decay via multiple bimolecular pathways with the formation of various dimeric products, as shown by the analysis of reaction products following the electrochemical oxidation of dG (71). In DNA, the dimerization of G•(-H) radicals is not likely and the lifetime of G•(-H) is thus quite long, up to ∼5 s (73). Under these conditions, the reaction of G(-H)• with NO2- might become more favorable at the micromolar to millimolar concentrations of NO2- encountered in cellular environments. In healthy humans, the levels of NO2- are 0.5-4 µM in plasma (30, 31), 0.4-60 µM in gastric juice, and 30-210 µM in saliva (33). Much higher levels of NO2- are detected during inflammation (32). Thus, the reaction with nitrite of DNA-bound G(-H)• radicals formed via oxidative reactions might represent important pathways of the generation of •NO2 from NO2-, and thus deserves further examination. Reactions of •NO2 Radicals with 8-Oxo-dG. The redox potential E°(•NO2/NO2-) ()1.04 V vs NHE) (58) is lower than that of guanine, E7[G•(-H)/G] ()1.29 V vs NHE) (55), the most easily oxidizable DNA base. Using pulse radiolysis technique, Pru¨tz et al. have shown (34) that in agreement with these potentials, •NO2 radicals do not react with intact DNA. However, •NO2 can induce damage to DNA lesions by reacting with oxidized nucleotides such as 8-oxo-dG. The latter is a stable product of the two-electron oxidation of guanosine. In neutral aqueous solutions, the redox potential (36) E7(8-oxo-dG•/8-oxodG) ()0.74 V vs NHE) is lower than the redox potential of •NO2, and thus, the direct one-electron oxidation of 8-oxo-dG by •NO2 is feasible. Kinetic measurements performed in this work have shown that 8-oxo-dG acts as a typical one-electron donor. The rate constants of 8-oxo-dG oxidation by strong oneelectron oxidants such as BPT•+, anisole•+, and thioanisole•+ radical cations (E° ) 1.62-1.45 V vs NHE) are in the range of 2.3-1.5 × 109 M-1 s-1 (Table 2). These radical cations with E° values of g1.45 V versus NHE can also oxidize the parent guanine base with similar rate constants of 1.7 × 109 M-1 s-1 (BPT•+; 40) and 1.45 × 109 M-1 s-1 (thioanisole•+; 55). However, in contrast to 8-oxo-dG which is easily oxidized by radical cations with an E° of 1.13-0.91 V versus NHE, the dG•(-H) neutral radical (E7 ) 1.29 V vs NHE) oxidizes 1,2,4-TMB (E° ) 1.13 V vs NHE) with a rate constant (55) of 6.3 × 108 M-1 s-1. Hence, in aqueous solutions, 8-oxo-dG is indeed more easily oxidizable than the parent guanine base. The rate constant of 8-oxo-dG oxidation by different radical cations decreases from 5.8 × 108 M-1 s-1 in the case of 1,2,4-TMB•+ (E° ) 1.13 V vs NHE) to 5 × 107 M-1 s-1 for promethazine•+ (E° ) 0.91 V vs NHE). However, these rate constants are greater by factors of 10-100 than the rate constant of 8-oxo-dG oxidation (5 × 106 M-1 s-1) by •NO2 radicals. As in the case of the back reaction (one-electron oxidation of NO2-), this slow rate of the electron transfer reaction of •NO2 radicals can be explained in terms of a small self-exchange rate constant and a high internal reorganization energy in the •NO2/ NO2- system (70); these factors account for the lower reactivity of •NO2 radicals in bimolecular outer sphere electron transfer reactions. The rate constant of 8-oxodG oxidation by •NO2 can be compared with the rate constants of oxidation of typical organic electron donors. Huie and Neta reported (74) that •NO2 radicals oxidize

NO2 as an Oxidizing Agent of 8-Oxo-dG

N,N′-dimethylaniline (E° ) 0.87 V vs NHE) and pphenylenediamine (E° ) 0.57 V vs NHE) at pH 9.6 with rate constants of 2.6 × 107 and 4.6 × 107 M-1 s-1, respectively. These rate constants are somewhat greater than the rate constant of 8-oxo-dG oxidation. In the case of 8-oxo-dG, the electron abstraction is accompanied by the partial deprotonation of 8-oxo-dG•+ radical cations. Hence, oxidation of 8-oxo-dG by •NO2 might also be considered in terms of a proton-coupled electron transfer reaction (48, 53), although it is not clear whether deprotonation either accompanies the electron transfer step or occurs subsequently (75). The combination of •NO2 radicals with other radicals is a very rapid reaction, and in many cases, the rates of these reactions are close to the diffusion-controlled limit (76). Nitrogen and/or oxygen atoms of the •NO2 radical can participate in the formation of chemical bonds with the target radical, because the unpaired electron is delocalized on both N and O atoms (77). Recently, Neta and their co-workers have discussed (78) the combination of •NO2 and CO3•-. In this reaction, the formation of a N-O bond results in the formation of stable molecules (NO3- and CO2). In the case of organic radicals, their combination with •NO2 can result in the formation of nitro compounds and nitrosooxy derivatives. For instance, Pru¨tz et al. have reported (34) that •NO2 reacts with tyrosine radicals with a rate constant of ∼3 × 109 M-1 s-1 and results in the formation of 3-nitrotyrosine. Both 8-nitro-G and 4,5-dihydro-5-hydroxy-4-(nitrosooxy)-2′deoxyguanosine have been isolated from the reaction mixtures of dG and peroxynitrite (79). In the case of 8-oxo-dG, reaction with •NO2 may also trigger a cascade of consecutive steps, thus generating the degradation products of 8-oxo-dG.

Acknowledgment. This work was supported by National Science Foundation Grant CHE-9700429 and by a grant from the Kresge Foundation.

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