title: Assessing protection against OP pesticides and nerve agents provided by wild-type HuPON1 purified from Trichoplusia ni larvae or induced via adenoviral infection.
abstract: Human paraoxonase-1 (HuPON1) has been proposed as a catalytic bioscavenger of organophosphorus (OP) pesticides and nerve agents. We assessed the potential of this enzyme to protect against OP poisoning using two different paradigms. First, recombinant HuPON1 purified from cabbage loopers (iPON1; Trichoplusia ni) was administered to guinea pigs, followed by exposure to at least 2 times the median lethal dose (LD(50)) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic metabolite of the OP pesticide chlorpyrifos. In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then exposed to sequential doses of GD, VX, or (as reported previously) diazoxon, the toxic metabolite of the OP pesticide diazinon. In both animal models, the exogenously added HuPON1 protected animals against otherwise lethal doses of the OP pesticides but not against the nerve agents. Together, the results support prior modeling and in vitro activity data which suggest that wild-type HuPON1 does not have sufficient catalytic activity to provide in vivo protection against nerve agents.
authors.affiliation: Physiology and Immunology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, United States.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Hodgins
authors.forename: Shane A
authors.initials: SA
authors.lastname: Kasten
authors.forename: Joshua
authors.initials: J
authors.lastname: Harrison
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Otto
authors.forename: Zeke P
authors.initials: ZP
authors.lastname: Oliver
authors.forename: Peter
authors.initials: P
authors.lastname: Rezk
authors.forename: Tony E
authors.initials: TE
authors.lastname: Reeves
authors.forename: Nageswararao
authors.initials: N
authors.lastname: Chilukuri
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cerasoli
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000493:pharmacokinetics; D043303:Aryldialkylphosphatase / Q000008:administration & dosage* / Q000235:genetics / Q000302:isolation & purification / Q000493:pharmacokinetics; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004390:Chlorpyrifos / Q000031:analogs & derivatives / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D009036:Moths; D010755:Organophosphates / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000302:isolation & purification / Q000493:pharmacokinetics; D012524:Sarin / Q000633:toxicity; D012999:Soman / Q000633:toxicity
chemical_list: D000931:Antidotes; D002619:Chemical Warfare Agents; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010575:Pesticides; D011994:Recombinant Proteins; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D012999:Soman; D012524:Sarin; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D004390:Chlorpyrifos; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate