den Hartog Gertjan J M, Haenen Guido R M M, Vegt Erik, van der Vijgh Wim J F, Bast Aalt
Department of Pharmacology and Toxicology, University Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands.
Chem Biol Interact. 2003 Mar 6;145(1):33-9. doi: 10.1016/s0009-2797(02)00160-6.
Cu,Zn-superoxide dismutase (SOD1) has been shown to be effective in several free radical mediated diseases, although some studies have pointed toward SOD1 toxicity at a high concentrations. In the present study, the balance between prevention and induction of damage by SOD1 has been investigated both in vitro and in vivo. In vitro superoxide was generated using xanthine/xanthine oxidase. In vivo superoxide was generated using the redox cycling compound doxorubicin. Furthermore, we determined the pharmacokinetics of lecithinized SOD1 (PC-SOD) in order to compare the results obtained in vivo with those obtained in vitro. It was found that in vitro high concentrations of SOD1 induce hydroxylation of coumarin 3-carboxylic acid (3-CCA). This could be caused by a peroxidative action of SOD1 or formation of the highly reactive hydroxyl radicals. Any signs of toxicity are absent in vivo because these concentrations are not reached. It can be concluded that SOD1 possesses a large therapeutic window and application of SOD1 or its derivatives for strengthening the body's defenses against oxidative stress in a variety of pathologies seems safe.
铜锌超氧化物歧化酶（SOD1）已被证明在几种自由基介导的疾病中有效，尽管一些研究指出高浓度时SOD1具有毒性。在本研究中，已在体外和体内研究了SOD1预防和诱导损伤之间的平衡。体外使用黄嘌呤/黄嘌呤氧化酶产生超氧化物。体内使用氧化还原循环化合物阿霉素产生超氧化物。此外，我们测定了卵磷脂化SOD1（PC-SOD）的药代动力学，以便将体内获得的结果与体外获得的结果进行比较。结果发现，体外高浓度的SOD1会诱导香豆素3-羧酸（3-CCA）的羟基化。这可能是由SOD1的过氧化作用或高活性羟基自由基的形成引起的。体内不存在任何毒性迹象，因为未达到这些浓度。可以得出结论，SOD1具有很大的治疗窗，在多种病理情况下应用SOD1或其衍生物来增强机体对氧化应激的防御似乎是安全的。
