Kim Sang Geon, Lee Chang Ho, Park Jeong Weon
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
J Toxicol Environ Health A. 2004 Dec;67(23-24):2013-24. doi: 10.1080/15287390490514732.
Previously, studies reported that depletion of cellular GSH by sulfur amino acid deprivation (SAAD) potentiated arsenic (As)-induced cytotoxicity through activation of mitogen-activated protein (MAP) kinases. Deprenyl (selegiline), a selective inhibitor of monoamine oxidase B that is responsible for oxidative metabolism of dopamine, has been used as a therapeutic agent for the treatment of Parkinson's disease. This study investigated (1) whether deprenyl inhibited As-induced toxicity or As toxicity that was potentiated by glutathione (GSH) depletion and (2) whether deprenyl affected MAP kinase activation. Deprenyl protected H4IIE cells against the toxicity induced by As + SAAD in a concentration-dependent manner, but not by As alone. Activation of JNK by SAAD or As, but not that of p38 kinase or ERK1/2, was inhibited by treatment of cells with deprenyl. The cells that had been exposed to As or SAAD exhibited decreases in mitochondrial permeability to rhodamine 123, which was restored by deprenyl treatment or transfection with the plasmid encoding a dominant negative mutant of JNK [JNK1( )]. Transfection of H4IIE cells with the JNK1( ) plasmid, however, failed to protect cells against As toxicity. These results showed that deprenyl inhibits As toxicity potentiated by cellular GSH depletion, but not the toxicity induced by As alone. The cytoprotective effect of deprenyl may be mediated with restoration of mitochondrial function via its inhibition of JNK1.
此前，有研究报道，通过硫氨基酸剥夺（SAAD）使细胞内谷胱甘肽（GSH）耗竭，可通过激活丝裂原活化蛋白（MAP）激酶增强砷（As）诱导的细胞毒性。司来吉兰（丙炔苯丙胺）是一种负责多巴胺氧化代谢的单胺氧化酶B的选择性抑制剂，已被用作治疗帕金森病的药物。本研究调查了：（1）丙炔苯丙胺是否抑制As诱导的毒性或由谷胱甘肽（GSH）耗竭增强的As毒性；（2）丙炔苯丙胺是否影响MAP激酶的激活。丙炔苯丙胺以浓度依赖的方式保护H4IIE细胞免受As + SAAD诱导的毒性，但对单独的As诱导的毒性无保护作用。用丙炔苯丙胺处理细胞可抑制SAAD或As诱导的JNK激活，但不抑制p38激酶或ERK1/2的激活。暴露于As或SAAD的细胞对罗丹明123的线粒体通透性降低，而丙炔苯丙胺处理或用编码JNK显性负突变体[JNK1( )]的质粒转染可使其恢复。然而，用JNK1( )质粒转染H4IIE细胞未能保护细胞免受As毒性。这些结果表明，丙炔苯丙胺可抑制细胞内GSH耗竭增强的As毒性，但不能抑制单独As诱导的毒性。丙炔苯丙胺的细胞保护作用可能是通过抑制JNK1恢复线粒体功能来介导的。
