Smith R A, Porteous C M, Coulter C V, Murphy M P
Department of Chemistry, University of Otago, Dunedin, New Zealand.
Eur J Biochem. 1999 Aug;263(3):709-16. doi: 10.1046/j.1432-1327.1999.00543.x.
Mitochondrial oxidative damage contributes significantly to a range of human disorders, including neurodegenerative diseases, ischaemia-reperfusion injury and ageing-associated dysfunction. To prevent this damage we have delivered a molecule containing the active antioxidant moiety of vitamin E to mitochondria. This was carried out by covalently coupling the antioxidant moiety to a lipophilic triphenylphosphonium cation. This mitochondrially targeted antioxidant, 2-[2-(triphenylphosphonio)ethyl]-3,4-dihydro-2, 5,7,8-tetramethyl-2H-1-benzopyran-6-ol bromide (TPPB), accumulated several-hundred fold within the mitochondrial matrix, driven by the organelle's large membrane potential. When cells were incubated with micromolar concentrations of TPPB, they accumulated millimolar concentrations within their mitochondria. The amount of TPPB taken up by mitochondria was approximately 80-fold greater than endogenous levels of vitamin E. Consequently the targeted derivative of vitamin E protected mitochondrial function from oxidative damage far more effectively than vitamin E itself. The mitochondrially targeted antioxidant TPPB has potential as an antioxidant therapy for disorders involving mitochondrial oxidative damage. It also suggests a new family of mitochondrially targeted antioxidants, redox-active and pharmacologically active molecules designed to prevent damage or manipulate mitochondrial function.
线粒体氧化损伤在一系列人类疾病中起重要作用，包括神经退行性疾病、缺血再灌注损伤和与衰老相关的功能障碍。为防止这种损伤，我们已将一种含有维生素E活性抗氧化部分的分子递送至线粒体。这是通过将抗氧化部分与亲脂性三苯基膦阳离子共价偶联来实现的。这种线粒体靶向抗氧化剂，2-[2-(三苯基膦基)乙基]-3,4-二氢-2,5,7,8-四甲基-2H-1-苯并吡喃-6-醇溴化物（TPPB），在细胞器的大膜电位驱动下，在线粒体基质中积累了数百倍。当细胞与微摩尔浓度的TPPB孵育时，它们在线粒体内积累了毫摩尔浓度。线粒体摄取的TPPB量比维生素E的内源性水平大约高80倍。因此，维生素E的靶向衍生物比维生素E本身更有效地保护线粒体功能免受氧化损伤。线粒体靶向抗氧化剂TPPB有潜力作为一种抗氧化疗法用于涉及线粒体氧化损伤的疾病。它还提示了一个新的线粒体靶向抗氧化剂家族，即设计用于防止损伤或操纵线粒体功能的具有氧化还原活性和药理活性的分子。
