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.