title: Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.
abstract: Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation.
authors.affiliation: Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Jan
authors.affiliation: Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States. Electronic address: jricha3@eohsi.rutgers.edu.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.affiliation: Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Baker
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mishin
authors.affiliation: Department of Environmental Health Science, New York Medical College, Valhalla, NY, United States.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ, United States.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Laskin
authors.affiliation: Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States. Electronic address: jlaskin@eohsi.rutgers.edu.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Laskin
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D065767:Activation, Metabolic; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D062025:Organophosphate Poisoning / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D010084:Oxidation-Reduction; D010261:Paraoxon / Q000378:metabolism / Q000633:toxicity; D010278:Parathion / Q000378:metabolism / Q000633:toxicity*; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D024483:Vitamin K 3 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D058851:GPI-Linked Proteins; D007306:Insecticides; D011994:Recombinant Proteins; D009249:NADP; D010278:Parathion; D024483:Vitamin K 3; D003577:Cytochrome P-450 Enzyme System; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C548246:Ache protein, rat; D010261:Paraoxon
keywords: Cytochrome P450 reductase; Cytochrome P450 system; Menadione; Parathion; Redox cycling