title: Paraquat neurotoxicity is distinct from that of MPTP and rotenone.
abstract: Paraquat, MPTP, and rotenone reproduce features of Parkinson's disease (PD) in experimental animals. The exact mechanisms by which these compounds damage the dopamine system are not firmly established, but selective damage to dopamine neurons and inhibition of complex I are thought to be involved. We and others have previously documented that the toxic metabolite of MPTP, MPP+, is transported into dopamine neurons through the dopamine transporter (DAT), while rotenone is not transported by DAT. We have also demonstrated the requirement for complex I inhibition and oxidative damage in the dopaminergic neurodegeneration produced by rotenone. Based on structural similarity to MPP+, it has been proposed that paraquat exerts selective dopaminergic toxicity through transport by the DAT and subsequent inhibition of mitochondrial complex I. In this study we report that paraquat is neither a substrate nor inhibitor of DAT. We also demonstrate that in vivo exposure to MPTP and rotenone, but not paraquat, inhibits binding of 3H-dihydrorotenone to complex I in brain mitochondria. Rotenone and MPP+ were both effective inhibitors of complex I activity in isolated brain mitochondria, while paraquat exhibited weak inhibitory effects only at millimolar concentrations. These data indicate that, despite the apparent structural similarity to MPP+, paraquat exerts its deleterious effects on dopamine neurons in a manner that is unique from rotenone and MPTP.
authors.affiliation: Center for Neurodegenerative Disease, School of Medicine and Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.forename: Yu
authors.initials: Y
authors.lastname: Quan
authors.forename: Todd B
authors.initials: TB
authors.lastname: Sherer
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Greenamyre
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D015259:Dopamine Agents / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006540:Herbicides / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010269:Paraquat / Q000378:metabolism / Q000633:toxicity*; D012402:Rotenone / Q000378:metabolism / Q000633:toxicity*; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D015259:Dopamine Agents; D006540:Herbicides; D007306:Insecticides; D012402:Rotenone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010269:Paraquat