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 (40 mg/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.

Novel approaches to mitigating parathion toxicity: targeting cytochrome P450–mediated metabolism with menadione

“…Thus, using recombinant enzymes, we found that menadione inhibits multiple human P450 isoforms from different subfamilies, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7 (see Fig. for an example of chemical redox cycling and the inhibition of CYP activity) . These data are consistent with earlier studies showing that menadione can inhibit CYP‐mediated aniline‐ p ‐hydroxylation and aminopyrine‐ N ‐demethylation in rat liver microsomes …”

“…Our laboratory has been characterizing the redox‐cycling activity of the p ‐quinone menadione (methyl‐1,4‐naphthoquinone), also known as vitamin K3 . In the presence of NADPH–cytochrome P450 reductase, menadione readily redox cycles, generating superoxide anion and hydrogen peroxide.…”

Reversible cholinesterase inhibitors as pretreatment for exposure to organophosphates. A review

“…It is among the most lethal OPC pesticides, fumigants and nematocides and is now banned in most countries due to its toxicity. Parathion is rapidly oxidized and desulfurated by the liver microsomal cytochrome P450 (CYP) system (CYP1A2, 2B6, and 3A4) forming paraoxon (Jan et al, ), which strongly inhibits AChE activity (Figure ). Similarly, the pesticide methyl‐parathion (metaphos), one of the most widely applied OPC pesticides, needs to be metabolized by CYP‐dependent oxygenases to methyl‐paraoxon (dimethyl 4‐nitrophenyl phosphate), which is also an extremely efficient AChE inhibitor (Garcia, Abu‐Qare, Meeker‐O'Connell, Borton, & Abou‐Donia, ; Isbister et al, ).…”

Role of the calcium plateau in neuronal injury and behavioral morbidities following organophosphate intoxication

“…However, these models did not focus on evaluating long‐term survival after lethal POX SE exposures. Development of OP SE models is also complicated by their variable pharmacokinetic and pharmacodynamics response, such as the challenges associated with parathion kinetics and differential metabolism . We wanted to further develop a reliable rat survival model for lethal OP exposure with SE that would replicate both the acute mortality and chronic morbidity associated with these agents.…”