Ou P, Tritschler H J, Wolff S P
Department of Medicine, University College London Medical School, U.K.
Biochem Pharmacol. 1995 Jun 29;50(1):123-6. doi: 10.1016/0006-2952(95)00116-h.
Thioctic (alpha-lipoic) acid (TA) is a drug used for the treatment of diabetic polyneuropathy in Germany. It has been proposed that TA acts as an antioxidant and interferes with the pathogenesis of diabetic polyneuropathy. We suggest that one component of its antioxidant activity requiring study is the direct transition metal-chelating activity of the drug. We found that TA had a profound dose-dependent inhibitory effect upon Cu(2+)-catalysed ascorbic acid oxidation (monitored by O2 uptake and spectrophotometrically at 265 nm) and also increased the partition of Cu2+ into n-octanol from an aqueous solution suggesting that TA forms a lipophilic complex with Cu2+. TA also inhibited Cu(2+)-catalysed liposomal peroxidation. Furthermore, TA inhibited intracellular H2O2 production in erythrocytes challenged with ascorbate, a process thought to be mediated by loosely chelated Cu2+ within the erythrocyte. These data, taken together, suggest that prior intracellular reduction of TA to dihydrolipoic acid is not an obligatory mechanism for an antioxidant effect of the drug, which may also operate via Cu(2+)-chelation. The R-enantiomer and racemic mixture of the drug (alpha-TA) generally seemed more effective than the S-enantiomer in these assays of metal chelation.
硫辛酸（α-硫辛酸，TA）在德国是一种用于治疗糖尿病性多发性神经病的药物。有人提出TA可作为抗氧化剂，干预糖尿病性多发性神经病的发病机制。我们认为，其抗氧化活性中一个需要研究的成分是该药物的直接过渡金属螯合活性。我们发现，TA对铜（Ⅱ）催化的抗坏血酸氧化具有显著的剂量依赖性抑制作用（通过监测氧气摄取和在265nm处进行分光光度法测定），并且还增加了铜离子从水溶液向正辛醇中的分配，这表明TA与铜形成了亲脂性复合物。TA还抑制了铜（Ⅱ）催化的脂质体过氧化。此外，TA抑制了用抗坏血酸盐刺激的红细胞内过氧化氢的产生，这一过程被认为是由红细胞内松散螯合的铜离子介导的。综合这些数据表明，TA在细胞内预先还原为二氢硫辛酸并非该药物发挥抗氧化作用的必要机制，该药物也可能通过铜（Ⅱ）螯合发挥作用。在这些金属螯合试验中，该药物的R-对映体和外消旋混合物（α-TA）通常似乎比S-对映体更有效。
