Direct and hydrogen peroxide-induced Chromium(V) oxidation of deoxyribose in single-stranded and double-stranded calf thymus DNA
Direct and hydrogen peroxide-induced Chromium(V) oxidation of deoxyribose in single-stranded and double-stranded calf thymus DNA
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DOI：
10.1021/tx970135r
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发表时间：
1997-12-01
影响因子：
4.1
通讯作者：
Wetterhahn, KE
中科院分区：
文献类型：
--
作者：
Sugden, KD;Wetterhahn, KE
本文研究了Cr（V）模型配合物[CrO（ehba）（2）]（-）对DNA的氧化损伤作用，以及在加入和不加入H_2O_2的情况下，C_1 ′、C_4 ′和C_5 ′氢原子夺取机制所产生的碱和糖产物的形成。用5，5-二甲基吡咯啉N-氧化物（DMPO）进行的EPR研究表明，单独的Cr（V）-ehba可以通过直接铬途径氧化自旋陷阱，而Cr（V）-ehba在H2 O2存在下的反应产生羟基自由基。单链（ss）和双链（ds）小牛胸腺DNA的直接（或金属中心）Cr（V）ehba氧化表明，以O-2依赖性方式形成硫代巴比妥酸反应性物质（TEARS）和乙醇酸，与C4 'H原子的提取一致。Cr（V）直接氧化DNA时，也存在少量的C1' H原子夺取机制，但没有C5' H原子夺取产物。直接Cr（V）氧化ss-和ds-DNA也导致所有四种核酸碱基的释放，其中在ds-DNA中优先释放嘧啶、胞嘧啶和胸腺嘧啶，但在ss-DNA中没有观察到碱基释放偏好。该碱释放是O-2-独立的，并且在本研究中不能被H原子提取机制所解释。Cr（V）-ehba与H2 O2和DNA的反应产生的产物与所测量的所有三种DNA氧化途径一致，即C1 '，C4'和C5' H原子提取。Cr（V）-ehba和H_2O_2也能介导DNA碱基的非优先释放，但对氧化敏感的嘌呤和鸟嘌呤除外。直接和H2 O2诱导的Cr（V）DNA氧化具有相反的底物偏好，直接Cr（V）氧化有利于ss-DNA，而H2 O2诱导的Cr（V）氧化损伤有利于ds-DNA。这些结果可能有助于解释铬（VI）的致癌机制，并有助于突出高价铬和氧基自由基之间的DNA氧化的差异和相似之处。
Oxidative DNA damage by a model Cr(V) complex, [CrO(ehba)(2)](-), with and without added H2O2, was investigated for the formation of base and sugar products derived from C1', C4', and C5' hydrogen atom abstraction mechanisms. EPR studies with 5,5-dimethylpyrroline N-oxide (DMPO) have shown that Cr(V)-ehba alone can oxidize the spin trap via a direct chromium pathway, whereas reactions of Cr(V)-ehba in the presence of H2O2 generated the hydroxyl radical. Direct (or metal-centered) Cr(V) ehba oxidation of single-stranded (ss) and double-stranded (ds) calf thymus DNA demonstrated the formation of thiobarbituric acid-reactive species (TEARS) and glycolic acid in an O-2-dependent manner, consistent with abstraction of the C4'H atom. A minor C1' H atom abstraction mechanism was also observed for direct Cr(V) oxidation of DNA, but no C5' H atom abstraction product was observed. Direct Cr(V) oxidation of ss-and ds-DNA also caused the release of all four nucleic acid bases with a preference for the pyrimidines cytosine and thymine in ds-DNA, but no base release preference was observed in ss-DNA. This base release was O-2-independent and could not be accounted for by the H atom abstraction mechanisms in this study. Reaction of Cr(V)-ehba with H2O2 and DNA yielded products consistent with all three DNA oxidation pathways measured, namely, C1', C4', and C5' H atom abstractions. Cr(V)-ehba and H2O2 also mediated a nonpreferential release of DNA bases with the exception of the oxidatively sensitive purine, guanine. Direct and H2O2-induced Cr(V) DNA oxidation had opposing substrate preferences, with direct Cr(V) oxidation favoring ss-DNA while H2O2-induced Cr(V) oxidative damage favored ds-DNA. These results may help explain the carcinogenic mechanism of chromium(VI) and serve to highlight the differences and similarities in DNA oxidation between high-valent chromium and oxygen-based radicals.