Fang Jianguo, Zhong Liangwei, Zhao Rong, Holmgren Arne
The Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):103-9. doi: 10.1016/j.taap.2005.02.022.
The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if alpha-tocopherol quinone (TQ), a product of alpha-tocopherol oxidation, is reduced by ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by ebselen selenol, generated from fast reduction of ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, alpha-tocopherolhydroquinone (TQH(2)), is a potent antioxidant. The thioredoxin system dependence of ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.
由硫氧还蛋白（Trx）、硫氧还蛋白还原酶（TrxR）和NADPH组成的硫氧还蛋白系统是一种强大的蛋白质二硫键还原酶系统，具有广泛的底物特异性。最近研究表明，含硒唑的药物依布硒啉是哺乳动物TrxR和Trx的底物。我们研究了α-生育酚氧化产物α-生育酚醌（TQ）在TrxR存在的情况下是否能被依布硒啉还原，因为TQ本身不是该酶的底物。在TrxR存在的情况下，依布硒啉对TQ的还原是由该酶对依布硒啉的快速还原产生的依布硒啉硒醇引起的。TQ本身没有抗氧化活性，而TQ的还原产物α-生育酚氢醌（TQH₂）是一种有效的抗氧化剂。文中还讨论了依布硒啉催化还原其他氧化物质（如过氧化氢、脱氢抗坏血酸和过氧亚硝酸盐）对硫氧还蛋白系统的依赖性。依布硒啉通过硫氧还蛋白系统还原TQ的能力是解释该药物在体内作为抗氧化剂作用的一种新机制。
