Adenovirus-Mediated Human Paraoxonase 1 Gene Transfer to Provide Protection Against the Toxicity of the Organophosphorus Pesticide Toxicant Diazoxon

Human paraoxonase1 (hPON1) is a potential therapeutic against the toxicity of organophosphorus (OP) pesticides and chemical warfare nerve agents. We tested whether PON1 gene transfer using adenovirus provides protection against the toxicity of the OP diazoxon. Using an adenovirus construct containin...

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Bibliographic Details
Main Authors: Duysen, E G, Parikh, K, Aleti, V, Manne, V, Lockridge, O, Chilukuri, N
Format: Report
Language:English
Subjects:
ADENOVIRUSES
CHEMICAL WARFARE AGENTS
DIAZOXON
GENE DELIVERY
GENETIC ENGINEERING
Genetic Engineering and Molecular Biology
Medicine and Medical Research
NERVE AGENTS
ORGANOPHOSPHATES
PARAOXNASE1
PESTICIDES
PROPHYLACTICS
REPRINTS
TOXICITY
Toxicology
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Summary:Human paraoxonase1 (hPON1) is a potential therapeutic against the toxicity of organophosphorus (OP) pesticides and chemical warfare nerve agents. We tested whether PON1 gene transfer using adenovirus provides protection against the toxicity of the OP diazoxon. Using an adenovirus construct containing hPON1 gene, we showed elevated levels of recombinant enzyme was secreted by 293A cells into culture medium and into the systemic circulation of mice. Western blotting revealed that the virally expressed hPON1 had the expected molecular weight of 45kDa. Recombinant hPON1 in mice was in complex with mouse high-density lipoprotein (HDL) and migrated more slowly than endogenous hPON1 in the human HDL complex. Mice injected with adenovirus expressed PON1 at 600-3480 U ml(-1) on day 5 post-treatment, which is 8-50 fold above endogenous. Six mice expressing hPON1 survived 2LD(50) doses of diazoxon. Four of the six mice survived a second dose of diazoxon (for a total of 4LD(50)) administered 24h later. In contrast, none of the three mice in the control group survived one 2LD(50) dose. These results show that hPON1 in mice functions as a prophylactic and offers significant protection against lethal doses of diazoxon. Published in Gene Therapy v18 p250-257, Mar 2011; published online 28 Oct 2010.