Glutathionyl- and hydroxyl radical formation coupled to the redox transitions of 1,4-naphthoquinone bioreductive alkylating agents during glutathione two-electron reductive addition.
Glutathionyl- and hydroxyl radical formation coupled to the redox transitions of 1,4-naphthoquinone bioreductive alkylating agents during glutathione two-electron reductive addition.
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在谷胱甘肽双电子还原加成过程中，谷胱甘肽和羟基自由基的形成与 1,4-萘醌生物还原烷基化剂的氧化还原转变耦合。
DOI：
10.1016/0003-9861(91)90211-z
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发表时间：
1991
影响因子：
3.9
通讯作者：
Cadenas,E
中科院分区：
文献类型：
--
作者：
Goin,J;Gibson,DD;McCay,PB;Cadenas,E
采用自旋捕获电子自旋共振（ESR）方法，研究了谷胱甘肽（GSH）还原加成2-和6-羟甲基-1，4-萘醌生物烷基化试剂后的氧化还原动力学参数，包括自氧化、GSH在芳基化反应中的消耗、巯基氧化生成谷胱甘肽二硫化物（GSSG）和自由基的形成.的位置的羟甲基取代基的苯型或quinidazole环的差异影响的初始速率的氢醌自氧化以及硫醇氧化。因此，在GSH还原加成到6-羟甲基-1，4-萘醌上的过程中，GSSG-和过氧化氢的形成速率明显高于2-羟甲基衍生物。然而，无论羟甲基取代基的位置如何，两种醌的分子终产物的分布和浓度是相同的。[O2]消耗[GSSG]形成的比率在两种情况下都高于1，从而表明发生了自氧化反应，而不是GSSG形成过程中所涉及的反应。用自旋探针5，5′-二甲基-1-吡咯啉-N-氧化物（DMPO）研究表明，GSH的氧化与上述氧化还原跃迁耦合，形成了不同结构的自由基，如羟基和巯基.这些被鉴定为相应的DMPO加合物。任一DMPO加合物的检测取决于GSH在反应混合物中的浓度：DMPO的羟基自由基加合物在低GSH浓度下占优势，而DMPO的巯基自由基加合物在高GSH浓度下占优势。前者加合物的生产是敏感的过氧化氢酶，而后者是敏感的超氧化物歧化酶以及过氧化氢酶。自由基形成耦合到硫醇氧化的相关性进行了讨论，在涉及的反应的热力学和动力学性质，以及在醌细胞毒性的潜在影响。
The kinetic parameters of the redox transitions subsequent to the two-electron transfer implied in the glutathione (GSH) reductive addition to 2-and 6-hydroxymethyl-1, 4-naphthoquinone bioalkylating agents were examined in terms of autoxidation, GSH consumption in the arylation reaction, oxidation of the thiol to glutathione disulfide (GSSG), and free radical formation detected by the spin-trapping electron spin resonance method. The position of the hydroxymethyl substituent in either the benzenoid or the quinonoid ring differentially influenced the initial rates of hydroquinone autoxidation as well as thiol oxidation. Thus, GSSG-and hydrogen peroxide formation during the GSH reductive addition to 6-hydroxymethyl-1, 4-naphthoquinone proceeded at rates substantially higher than those observed with the 2-hydroxymethyl derivative. The distribution and concentration of molecular end products, however, was the same for both quinones, regardless of the position of the hydroxymethyl substituent. The [O 2] consumed [GSSG] formed ratio was above unity in both cases, thus indicating the occurrence of autoxidation reactions other than those involved during GSSG formation. EPR studies using the spin probe 5, 5′-dimethyl-1-pyrroline-N-oxide (DMPO) suggested that the oxidation of GSH coupled to the above redox transitions involved the formation of radicals of differing structure, such as hydroxyl and thiyl radicals. These were identified as the corresponding DMPO adducts. The detection of either DMPO adduct depended on the concentration of GSH in the reaction mixture: the hydroxyl radical adduct of DMPO prevailed at low GSH concentrations, whereas the thiyl radical adduct of DMPO prevailed at high GSH concentrations. The production of the former adduct was sensitive to catalase, whereas that of the latter was sensitive to superoxide dismutase as well as to catalase. The relevance of free radical formation coupled to thiol oxidation is discussed in terms of the thermodynamic and kinetic properties of the reactions involved as well as in terms of potential implications in quinone cytotoxicity.