Title: Engineered recombinant human paraoxonase 1 (rHuPON1) purified from Escherichia coli protects against organophosphate poisoning.
Authors: Stevens, Richard C; Suzuki, Stephanie M; Cole, Toby B; Park, Sarah S; Richter, Rebecca J; Furlong, Clement E
Published In Proc Natl Acad Sci U S A, (2008 Sep 2)
Abstract: The high-density lipoprotein-associated enzyme paraoxonase 1 (PON1) hydrolyzes lactones, aromatic esters, and neurotoxic organophosphorus (OP) compounds, including insecticide metabolites and nerve agents. Experiments with mice lacking PON1 (PON1(-/-) mice) have established that plasma PON1 protects against chlorpyrifos/chlorpyrifos-oxon and diazinon/diazoxon (DZO) exposure but does not protect against parathion/paraoxon or nerve agents. The catalytic efficiency of PON1 determines whether or not it will protect against a given OP exposure. Expression of active recombinant human PON1 (rHuPON1) in Escherichia coli provides a system in which PON1 can be engineered to achieve a catalytic efficiency sufficient to protect against or treat specific OP exposures. Here, we describe the generation of highly purified engineered rHuPON1(K192) that protects against DZO exposure when injected into PON1(-/-) mice. The injected rHuPON1 is nontoxic, persists in serum for at least 2 days after injection, and provides protection against DZO exposures of at least three times the median lethal dose value.
PubMed ID: 18711144
MeSH Terms: Animals; Aryldialkylphosphatase/blood; Aryldialkylphosphatase/isolation & purification*; Aryldialkylphosphatase/metabolism; Aryldialkylphosphatase/pharmacology*; Electrophoresis, Polyacrylamide Gel; Escherichia coli/metabolism*; Humans; Hydrolysis; Injections, Intraperitoneal; Kinetics; Mice; Phosphoric Acid Esters/poisoning*; Protein Engineering*; Recombinant Proteins/administration & dosage; Recombinant Proteins/isolation & purification*; Recombinant Proteins/metabolism; Recombinant Proteins/pharmacology*; Staphylococcal Protein A/metabolism