title: Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione.
abstract: Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.
authors.affiliation: Department of Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, New Jersey.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.affiliation: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio. jrichardson@neomed.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.affiliation: Department of Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, New Jersey.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Baker
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mishin
authors.affiliation: Department of Environmental Health Science, New York Medical College, Valhalla, New York.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
authors.affiliation: Department of Environmental and Occupational Health, Rutgers University School of Public Health, Piscataway, New Jersey. jlaskin@eohsi.rutgers.edu.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity; D062025:Organophosphate Poisoning / Q000188:drug therapy / Q000201:enzymology; D010278:Parathion / Q000378:metabolism / Q000633:toxicity*; D024483:Vitamin K 3 / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007306:Insecticides; D010278:Parathion; D024483:Vitamin K 3; D003577:Cytochrome P-450 Enzyme System
keywords: menadione; organophosphorus pesticides; paraoxon; parathion; redox cycling