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

Jackson, Colin; Carville, Angela; Ward, Jeanine; Mansfield, Keith; Ollis, David; Khurana, Tejvir; Bird, Steven

Description

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...[Show more]

dc.contributor.authorJackson, Colin
dc.contributor.authorCarville, Angela
dc.contributor.authorWard, Jeanine
dc.contributor.authorMansfield, Keith
dc.contributor.authorOllis, David
dc.contributor.authorKhurana, Tejvir
dc.contributor.authorBird, Steven
dc.date.accessioned2015-12-10T23:07:00Z
dc.identifier.issn0300-483X
dc.identifier.urihttp://hdl.handle.net/1885/62906
dc.description.abstractOrganophosphorus (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 1.2. mg/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.
dc.publisherElsevier
dc.sourceToxicology
dc.titleUse of OpdA, an organophosphorus (OP) hydrolase, prevents lethality in an African green monkey model of acute OP poisoning
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume317
dc.date.issued2014
local.identifier.absfor060113 - Synthetic Biology
local.identifier.ariespublicationu4005981xPUB749
local.type.statusPublished Version
local.contributor.affiliationJackson, Colin, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationCarville, Angela, Harvard Medical School
local.contributor.affiliationWard, Jeanine, University of Massachusetts Medical School
local.contributor.affiliationMansfield, Keith, Harvard Medical School
local.contributor.affiliationOllis, David, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationKhurana, Tejvir, University of Pennsylvania
local.contributor.affiliationBird, Steven, University of Massachusetts Medical School
local.description.embargo2037-12-31
local.bibliographicCitation.startpage1
local.bibliographicCitation.lastpage5
local.identifier.doi10.1016/j.tox.2014.01.003
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
dc.date.updated2015-12-10T08:58:12Z
local.identifier.scopusID2-s2.0-84893451121
local.identifier.thomsonID000334087100001
CollectionsANU Research Publications

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