Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.
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Jan YH, Richardson JR, Baker AA, Mishin V, Heck DE, Laskin DL, Laskin JD
Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication.
Toxicol Appl Pharmacol. 2015 Oct 1;288(1):114-20. doi: 10.1016/j.taap.2015.07.023. Epub 2015 Jul 23.
- PubMed ID
- 26212258 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Menadione Cytochrome P450 1A1 Protein Humans UnknownInhibitorInducerDetails Menadione Cytochrome P450 1A2 Protein Humans UnknownInhibitorInducerDetails Menadione Cytochrome P450 1B1 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2A6 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2B6 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2C19 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2C8 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2C9 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2D6 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 2E1 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 3A4 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 3A5 Protein Humans UnknownInhibitorDetails Menadione Cytochrome P450 3A7 Protein Humans UnknownInhibitorDetails