Use of OpdA, an organophosphorus (OP) hydrolase, prevents lethality in an African green monkey model of acute OP poisoning.
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.
Research School of Chemistry, Australian National University, Australian Capital Territory 0200, Australia. Electronic address: cjackson@rsc.anu.edu.au.
Colin J
CJ
Jackson
New England Regional Primate Research Center, Harvard Medical School, Southboro, MA 01772, USA. Electronic address: aalcarville@gmail.com.
Angela
A
Carville
University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01655, USA. Electronic address: Jeanine.ward@umassmemorial.org.
Jeanine
J
Ward
New England Regional Primate Research Center, Harvard Medical School, Southboro, MA 01772, USA. Electronic address: Keith.mansfield@novartis.com.
Keith
K
Mansfield
Research School of Chemistry, Australian National University, Australian Capital Territory 0200, Australia. Electronic address: ollis@rsc.anu.edu.au.
David L
DL
Ollis
Department of Physiology & Pennsylvania Muscle Institute, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. Electronic address: tsk@mail.med.upenn.edu.
Tejvir
T
Khurana
University of Massachusetts Medical School, 55 Lake Avenue, Worcester, MA 01655, USA. Electronic address: steven.bird@umassmemorial.org.
Steven B
SB
Bird
D000110:Acetylcholinesterase / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D060054:Agrobacterium / Q000201:enzymology*; D000818:Animals; D000931:Antidotes / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use*; D002522:Chlorocebus aethiops; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D003864:Depression, Chemical; D004006:Dichlorvos / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006339:Heart Rate / Q000187:drug effects; D006867:Hydrolases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use*; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D010575:Pesticides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000627:therapeutic use; D056152:Respiratory Rate / Q000187:drug effects; D012720:Severity of Illness Index; D013379:Substrate Specificity; D016019:Survival Analysis
D000931:Antidotes; D001426:Bacterial Proteins; D002800:Cholinesterase Inhibitors; D010575:Pesticides; D011994:Recombinant Proteins; D004006:Dichlorvos; D006867:Hydrolases; D000110:Acetylcholinesterase
Dichlorvos; Hydrolysis; Monkey; Organophosphorus; Pesticide