代谢
从Cu(II)配合物与生物还原剂如抗坏血酸、谷胱甘肽、乙酰半胱氨酸和对苯二酚的反应中产生羟基自由基（.OH）已被电子自旋共振（ESR）自旋捕获实验所证实。所使用的Cu(II)配合物包括：Cu(II)-(CyHH)2 (CyHH, 环(L-组氨酸-L-组氨酸))、Cu(II)(OP)2 (OP, 邻菲啰啉)、Cu(II)(HGG) (HGG, L-组氨酸-甘氨酰甘氨酸)和Cu(II)(en)2 (en, 乙二胺)。在自旋捕获剂POBN和二甲亚砜的存在下，抗坏血酸与所有在此使用的Cu(II)配合物反应生成了alpha-(吡啶-4-N-氧化物)-N-叔丁基氮氧化物（POBN-CH3）的甲基自由基加成物，表明产生了.OH。谷胱甘肽、N-乙酰半胱氨酸和对苯二酚与Cu(II)(CyHH)2和Cu(II)(OP)2反应生成了POBN-CH3，而这些还原剂与Cu(II)(HGG)或Cu(II)(en)2没有反应。在相同的条件下，研究了Cu(II)配合物与还原剂反应混合物引起的DNA链断裂。将抗坏血酸添加到这四种Cu(II)配合物和DNA的混合物中，导致了DNA链的断裂。在所使用的浓度范围内，谷胱甘肽、N-乙酰半胱氨酸或对苯二酚与Cu(II)-(HGG)或Cu(II)(en)2的反应混合物没有引起DNA链断裂。这里得到的结果表明POBN-CH3的形成与DNA链断裂之间存在良好的相关性。因此，DNA链断裂可能是由一些Cu(II)配合物在氧气的条件下与生物还原剂反应产生的.OH引起的。由于抗坏血酸、谷胱甘肽和N-乙酰半胱氨酸存在于活细胞中，一些Cu(II)配合物可能能够在这些还原剂存在的情况下引发DNA损伤。
The generation of hydroxyl radicals (.OH) from the reaction of Cu(II) complexes with biological reductants such as ascorbic acid, glutathione, acetylcysteine, and hydroquinone was confirmed by spin-trapping experiments using electron spin resonance (ESR). The following Cu(II) complexes were used: Cu(II)-(CyHH)2 (CyHH, cyclo(L-histidyl-L-histidyl)), Cu(II)(OP)2 (OP, o-phenanthroline), Cu(II)(HGG) (HGG, L-histidyl-glycylglycine), and Cu(II)(en)2 (en, ethylenediamine). The methyl radical adduct of alpha-(pyridyl-4-N-oxide)-N-tert-butylnitrone (POBN-CH3) was obtained from the reaction of ascorbic acid with all Cu(II) complexes used here in the presence of a spin trap, POBN, and dimethyl sulfoxide, indicating the generation of .OH. Glutathione, N-acetylcysteine, and hydroquinone reacted with both Cu(II)(CyHH)2 and Cu(II)(OP)2 to generate POBN-CH3, while these reductants did not react with either Cu(II)(HGG) or Cu(II)(en)2. The DNA strand scission caused by reaction mixtures of Cu(II) complexes with reductants was investigated under the same conditions as the ESR spin-trapping experiments. Addition of ascorbic acid to mixtures of these four Cu(II) complexes and DNA resulted in DNA strand breakage. Reaction mixtures of glutathione, N-acetylcysteine, or hydroquinone with Cu(II)-(HGG) or Cu(II)(en)2 did not cause DNA strand scission within the concentration range used. The results obtained here suggest that there is a good correlation between POBN-CH3 formation and DNA strand scission. Thus, DNA strand scission may be caused by .OH generated from the reaction of some Cu(II) complexes with biological reductants under aerobic conditions. Since ascorbic acid, glutathione, and N-acetylcysteine are present in living cells, some Cu(II) complexes may be capable of initiating DNA damage in the presence of these reductants.
来源:Hazardous Substances Data Bank (HSDB)
