ToxSci Advance Access originally published online on October 3, 2006
Toxicological Sciences 2007 95(1):163-171; doi:10.1093/toxsci/kfl125
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Divergent Mechanisms of Paraquat, MPP+, and Rotenone Toxicity: Oxidation of Thioredoxin and Caspase-3 Activation
,¶,1
* Center for Neurodegenerative Disease, School of Medicine, Emory University, Atlanta, Georgia 30322
Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322
Department of Pediatrics, Emory University, Atlanta, Georgia 30322
Department of Medicine and Clinical Biomarkers Laboratory, Emory University, Atlanta, Georgia 30322
¶ Department of Environmental and Occupational Medicine, University of Medicine and Dentistry-New Jersey/Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854
1 To whom correspondence should be addressed at Emory University Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, Room 505, 615 Michael Street Atlanta, GA 30322. Fax: (404) 727-3728. E-mail: gary.miller{at}emory.edu.
Received August 16, 2006; accepted September 30, 2006
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Abstract |
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Paraquat, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, and rotenone have been shown to reproduce several features of Parkinson's disease in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study, we show that paraquat specifically oxidized the cytosolic form of thioredoxin and activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, 1-methyl-4-phenylpyridinium (MPP+) and rotenone oxidized the mitochondrial form of thioredoxin but did not activate JNK-mitogen–activated protein kinase and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP+ and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.
Key Words: Paraquat; Parkinson's disease; MPTP; rotenone; thioredoxin; MAPK.
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