Assessing protection against OP pesticides and nerve agents provided by wild-type HuPON1 purified from Trichoplusia ni larvae or induced via adenoviral infection

• Published in: Chemico-biological interactions 2013-03, Vol.203 (1), p.177-180
• Main Authors: Hodgins, Sean M., Kasten, Shane A., Harrison, Joshua, Otto, Tamara C., Oliver, Zeke P., Rezk, Peter, Reeves, Tony E., Chilukuri, Nageswararao, Cerasoli, Douglas M.
• Format: Article
• Language: English
• Subjects: Adenovirus; animal models; Animals; Antidotes - administration & dosage; Antidotes - pharmacokinetics; Aryldialkylphosphatase - administration & dosage; Aryldialkylphosphatase - genetics; Aryldialkylphosphatase - isolation & purification; Aryldialkylphosphatase - pharmacokinetics; Brassica; catalytic activity; Catalytic bioscavenger; Chemical Warfare Agents - toxicity; chlorpyrifos; Chlorpyrifos - analogs & derivatives; Chlorpyrifos - toxicity; diazinon; Guinea Pigs; Humans; In vivo efficacy; larvae; lethal dose 50; Male; metabolites; Mice; Moths; Nerve agent; nerve tissue; Organophosphates - toxicity; Organophosphorus; Organophosphorus Compounds - toxicity; Paraoxonase 1; Pesticides - toxicity; poisoning; Recombinant Proteins - administration & dosage; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacokinetics; Sarin - toxicity; Soman - toxicity; Trichoplusia ni
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2012.10.015

► HuPON1 from insect cells protects guinea pigs from OP pesticide toxicity. ► HuPON1 from insect cells does not protect guinea pigs from OP nerve agents. ► Adenovirus-induced HuPON1 does not protect mice from OP nerve agents. 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 2times the median lethal dose (LD50) 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.