ENZYMES HYDROLYZING ORGANOPHOSPHATES AS POTENTIAL CATALYTIC SCAVENGERS AGAINST ORGANOPHOSPHATE POISONING

Enzymes hydrolyzing organophosphates could be used as catalytic scaven gers for treatment of organophosphate poisoning and for decontaminatio n. Two organophosphorus hydrolases (OPH) were selected: the Flavobacte rium sp./Pseudomonas diminuta phosphotriesterase (PTE) and human parao xonase (HuPON). Genes encoding these enzymes were cloned and functiona l recombinant enzymes expressed. PTE was expressed in E. coli. Natural HuPON was purified from human plasma; recombinant HuPON was expressed in human embryonic kidney 293 T cells. Although HuPON displays intere sting catalytic properties, a site-directed mutagenesis program was un dertaken to improve its catalytic efficiency. PTE has high efficiency in hydrolysis of organophosphates, including nerve agents. PTE injecte d in rat has a half-life of 100 min. However, to overcome pharmacokine tic problems of injected OPH and/or immunological incompatibility, the model enzyme (recombinant PTE) was immobilized onto a hollow-fiber re actor. This reactor designed for extracorporeal blood circulation is u nder experimentation for post-exposure detoxification. ((C) Elsevier, Paris).