Novel Approaches To Mitigating Parathion Toxicity: Targeting Cytochrome P450-mediated Metabolism With Menadione

Title

Novel Approaches To Mitigating Parathion Toxicity: Targeting Cytochrome P450-mediated Metabolism With Menadione

Creator

Jan Y H; Richardson J R; Baker A A; Mishin V; Heck D E; Laskin D L; Laskin J D

Publisher

Countermeasures against Chemical Threats Ii

Date

2016
2016

Description

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.

Subject

acetylcholinesterase; agents; chlorcyclizine; cytotoxicity; enzyme; inhibition; menadione; organophosphate exposure; organophosphorus; paraoxon; parathion; pesticides; reactivators; redox cycling; reductase; Super oxide

Identifier

Format

Book Chapter

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

80-86

Volume

1378

Citation

Jan Y H; Richardson J R; Baker A A; Mishin V; Heck D E; Laskin D L; Laskin J D, “Novel Approaches To Mitigating Parathion Toxicity: Targeting Cytochrome P450-mediated Metabolism With Menadione,” NEOMED Bibliography Database, accessed June 22, 2021, https://neomed.omeka.net/items/show/10328.

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