Use of OpdA, an organophosphorus (OP) hydrolase, prevents lethality in an African green monkey model of acute OP poisoning

Toxicology. 2014 Mar 20;317:1-5. doi: 10.1016/j.tox.2014.01.003. Epub 2014 Jan 18.

Abstract

Organophosphorus (OP) pesticides are a diverse class of acetylcholinesterase (AChE) inhibitors that are responsible for tremendous morbidity and mortality worldwide, killing approximately 300,000 people annually. Enzymatic hydrolysis of OPs is a potential therapy for acute poisoning. OpdA, an OP hydrolase isolated from Agrobacterium radiobacter, has been shown to decrease lethality in rodent models of OP poisoning. This study investigated the effects of OpdA on AChE activity, plasma concentrations of OP, and signs of toxicity after administration of dichlorvos to nonhuman primates. A dose of 75 mg/kg dichlorvos given orally caused apnea within 10 min with a progressive decrease in heart rate. Blood AChE activity decreased to zero within 10 min. Respirations and AChE activity did not recover. The mean dichlorvos concentration rose to a peak of 0.66 μg/ml. Treated monkeys received 1.2mg/kg OpdA iv immediately after poisoning with dichlorvos. In Opda-treated animals, heart and respiratory rates were unchanged from baseline over a 240-minute observation period. AChE activity slowly declined, but remained above 25% of baseline for the entire duration. Dichlorvos concentrations reached a mean peak of 0.19 μg/ml at 40 min after poisoning and decreased to a mean of 0.05 μg/ml at 240 min. These results show that OpdA hydrolyzes dichlorvos in an African green monkey model of lethal poisoning, delays AChE inhibition, and prevents lethality.

Keywords: Dichlorvos; Hydrolysis; Monkey; Organophosphorus; Pesticide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcholinesterase / blood
  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism
  • Agrobacterium / enzymology*
  • Animals
  • Antidotes / isolation & purification
  • Antidotes / metabolism
  • Antidotes / therapeutic use*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / isolation & purification
  • Bacterial Proteins / metabolism
  • Bacterial Proteins / therapeutic use*
  • Chlorocebus aethiops
  • Cholinesterase Inhibitors / blood
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacokinetics
  • Cholinesterase Inhibitors / toxicity
  • Depression, Chemical
  • Dichlorvos / blood
  • Dichlorvos / metabolism
  • Dichlorvos / pharmacokinetics
  • Dichlorvos / toxicity
  • Disease Models, Animal*
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Heart Rate / drug effects
  • Hydrolases / genetics
  • Hydrolases / isolation & purification
  • Hydrolases / metabolism
  • Hydrolases / therapeutic use*
  • Hydrolysis / drug effects
  • Male
  • Organophosphate Poisoning / drug therapy*
  • Organophosphate Poisoning / physiopathology
  • Pesticides / blood
  • Pesticides / metabolism*
  • Pesticides / pharmacokinetics
  • Pesticides / toxicity
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / therapeutic use
  • Respiratory Rate / drug effects
  • Severity of Illness Index
  • Substrate Specificity
  • Survival Analysis

Substances

  • Antidotes
  • Bacterial Proteins
  • Cholinesterase Inhibitors
  • Pesticides
  • Recombinant Proteins
  • Dichlorvos
  • Hydrolases
  • Acetylcholinesterase