Al-Gonaiah Majed, Smith Robert A, Stone Trevor W
Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK.
Brain Res. 2009 Jul 14;1280:33-42. doi: 10.1016/j.brainres.2009.05.024. Epub 2009 May 18.
The oxidation of xanthine by xanthine oxidase (XO) or xanthine dehydrogenase represents an important source of reactive oxygen species (ROS), which contribute to the damaging consequences of cerebral ischemia, inflammation, and neurodegenerative disorders. However, both enzymes are also able to act on reduced nicotinamide adenine dinucleotide (NADH). The FAD binding site to which NADH binds is distinct from that of the xanthine binding site. We report that the combination of xanthine oxidase and NADH is toxic to cultures of cerebellar granule neurons. Protection by superoxide dismutase (Cu,Zn-SOD or Mn-SOD) or catalase indicates mediation of the toxicity by superoxide and hydrogen peroxide. In addition, pre-incubating XO with EDTA at concentrations as low as 2 microM, prevented the toxicity, indicating that a metal contaminating XO is involved in producing the toxic effects of XO/NADH. It is possible that such a metal might play a role in the toxicity of XO in vivo.
黄嘌呤氧化酶（XO）或黄嘌呤脱氢酶催化黄嘌呤氧化是活性氧（ROS）的一个重要来源，ROS会导致脑缺血、炎症和神经退行性疾病的损伤后果。然而，这两种酶也能够作用于还原型烟酰胺腺嘌呤二核苷酸（NADH）。NADH结合的黄素腺嘌呤二核苷酸（FAD）结合位点与黄嘌呤结合位点不同。我们报告黄嘌呤氧化酶和NADH的组合对小脑颗粒神经元培养物有毒性。超氧化物歧化酶（铜锌超氧化物歧化酶或锰超氧化物歧化酶）或过氧化氢酶的保护作用表明超氧化物和过氧化氢介导了毒性。此外，用低至2微摩尔浓度的乙二胺四乙酸（EDTA）预孵育XO可防止毒性，这表明污染XO的一种金属参与产生XO/NADH的毒性作用。这样一种金属可能在XO的体内毒性中起作用。
