Deprenyl, a therapeutic agent for Parkinson's disease, inhibits arsenic toxicity potentiated by GSH depletion via inhibition of JNK activation.
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.
Kim
Sang Geon
SG
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea. sgk@snu.ac.kr
Lee
Chang Ho
CH
Park
Jeong Weon
JW
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001151:Arsenic / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D018929:Cell Culture Techniques; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology; D048670:MAP Kinase Kinase 4; D008928:Mitochondria / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000494:pharmacology*; D051381:Rats; D012642:Selegiline / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000978:Antiparkinson Agents; D012642:Selegiline; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D005978:Glutathione; D001151:Arsenic