title: Engineered recombinant human paraoxonase 1 (rHuPON1) purified from Escherichia coli protects against organophosphate poisoning.
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.
authors: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195-7720, USA.
authors: Richard C
authors: RC
authors: Stevens
authors: Stephanie M
authors: SM
authors: Suzuki
authors: Toby B
authors: TB
authors: Cole
authors: Sarah S
authors: SS
authors: Park
authors: Rebecca J
authors: RJ
authors: Richter
authors: Clement E
authors: CE
authors: Furlong
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007274:Injections, Intraperitoneal; D007700:Kinetics; D051379:Mice; D062025:Organophosphate Poisoning; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D013205:Staphylococcal Protein A / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D013205:Staphylococcal Protein A; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human