Nitrogen Dioxide as an Oxidizing Agent of 8-Oxo-7,8-dihydro-2'-deoxyguanosine but Not of 2'-Deoxyguanosine

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• 作者：Vladimir Shafirovich ; Jean Cadet ; Didier Gasparutto ; Alexander Dourandin ; and Nicholas E. Geacintov
• 刊名：Chemical Research in Toxicology
• 出版年：2001
• 出版时间：February 2001
• 年：2001
• 卷：14
• 期：2
• 页码：233 - 241
• 全文大小：103K
• 年卷期：v.14,no.2(February 2001)
• ISSN：1520-5010

文摘

The redox reactions of guanine and its widely studied oxidation product, the 8-oxo-7,8-dihydroderivative, are of significant importance for understanding the mechanisms of oxidative damagein 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 usednanosecond laser flash photolysis to demonstrate that neutral radicals, dGMP(-H), derivedby the one-electron oxidation and deprotonation of dGMP, can oxidize nitrite anions (NO₂^-) tothe nitrogen dioxide radical NO₂. In turn, we show that NO₂ can give rise to a one-electronoxidation of 8-oxo-G, but not of dGMP. The one-electron oxidation of dGMP was initiated bya radical cation generated by the laser pulse-induced photoionization of a pyrene derivativewith enhanced water solubility, 7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene (BPT). ThedGMP(-H) neutral radicals formed via deprotonation of the dGMP⁺ radical cations andidentified by their characteristic transient absorption spectrum (_max ~ 310 nm) oxidize nitriteanions with a rate constant of (2.6 ± 0.3) × 10⁶ M^-1 s^-1. The 8-oxo-dG is oxidized by NO₂ witha rate constant of (5.3 ± 0.5) × 10⁶ M^-1 s^-1. The 8-oxo-dG(-H) neutral radicals thus generatedare clearly identified by their characteristic transient absorption spectra (_max ~ 320 nm). Therate constant of 8-oxo-dG oxidation (k₁₂) by the NO₂ one-electron oxidant (the NO₂/NO₂^- redoxpotential, E 1.04 V vs NHE) is lower than k₁₂ for a series of oxidizing aromatic radicalcations with known redox potentials. The k₁₂ values for 8-oxo-dG oxidation by different aromaticradical cations derived from the photoionization of their parent compounds depend on the redoxpotentials of the latter, which were in the range of 0.8-1.6 V versus NHE. The magnitude ofk₁₂ 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 thefurther oxidative damage of 8-oxo-dG in DNA in cellular environments, are discussed.