Murphy Tonya C, Amarnath Venkataraman, Picklo Matthew J
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58203, USA.
J Neurochem. 2003 Mar;84(6):1313-21. doi: 10.1046/j.1471-4159.2003.01628.x.
4-hydroxy-trans-2-nonenal (HNE) is a neurotoxic product of lipid peroxidation whose levels are elevated in multiple neurodegenerative diseases and CNS trauma. The detoxification of HNE may take the route of glutathione conjugation to the C3 carbon and the oxidation or reduction of the C1 aldehyde. In this work, we examined whether the oxidation of HNE to its corresponding carboxylic acid, 4-hydroxy-trans-2-nonenoate (HNEAcid) was detoxifying event, if it occurred in rat cerebral cortex, and in which subcellular compartments. Our results show that HNEAcid did not form protein adducts and was non-toxic to Neuro 2A cells. HNEAcid formation occurred in rat cerebral cortex slices following exposure to HNE in a time-dependent and dose-dependent fashion. Homogenate studies indicated that HNEAcid formation was NAD+ dependent. Subcellular fractionation demonstrated that mitochondria had the highest specific activity for HNEAcid formation with a KM of 21 micro m HNE. These data indicate that oxidation of HNE to its corresponding acid is a major detoxification pathway of HNE in the CNS and that mitochondria play a role in this process.
4-羟基反式-2-壬烯醛（HNE）是脂质过氧化的一种神经毒性产物，其水平在多种神经退行性疾病和中枢神经系统创伤中会升高。HNE的解毒可能通过谷胱甘肽与C3碳结合以及C1醛的氧化或还原途径进行。在这项研究中，我们研究了HNE氧化为其相应的羧酸4-羟基反式-2-壬烯酸（HNE酸）是否是一种解毒过程，是否发生在大鼠大脑皮层以及发生在哪些亚细胞区室中。我们的结果表明，HNE酸不会形成蛋白质加合物，并且对Neuro 2A细胞无毒。在大鼠大脑皮层切片中，暴露于HNE后，HNE酸的形成呈时间依赖性和剂量依赖性。匀浆研究表明，HNE酸的形成依赖于NAD⁺。亚细胞分级分离显示，线粒体对HNE酸形成的比活性最高，其对HNE的米氏常数为21微摩尔。这些数据表明，HNE氧化为其相应的酸是中枢神经系统中HNE的主要解毒途径，并且线粒体在这一过程中发挥作用。
