title: Thiol-reactivity of the fungicide maneb.
abstract: Maneb (MB) is a manganese-containing ethylene bis-dithiocarbamate fungicide that is implicated as an environmental risk factor for Parkinson's disease, especially in combination with paraquat (PQ). Dithiocarbamates inhibit aldehyde dehydrogenases, but the relationship of this to the combined toxicity of MB + PQ is unclear because PQ is an oxidant and MB activates Nrf2 and increases cellular GSH without apparent oxidative stress. The present research investigated the direct reactivity of MB with protein thiols using recombinant thioredoxin-1 (Trx1) as a model protein. The results show that MB causes stoichiometric loss of protein thiols, reversibly dimerizes the protein and inhibits its enzymatic activity. MB reacted at similar rates with low-molecular weight, thiol-containing chemicals. Together, the data suggest that MB can potentiate neurotoxicity of multiple agents by disrupting protein thiol functions in a manner analogous to that caused by oxidative stress, but without GSH depletion.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322, USA ; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Roede
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
mesh_terms: D005659:Fungicides, Industrial / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008344:Maneb / Q000737:chemistry* / Q000378:metabolism; D010269:Paraquat / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D005659:Fungicides, Industrial; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; D008344:Maneb; D013879:Thioredoxins; D010269:Paraquat
keywords: Dithiocarbamate; Parkinson's disease; Pesticide; Thiol; Toxicity