Catalytic Bioscavengers Against Toxic Esters, an Alternative Approach for Prophylaxis and Treatments of Poisonings

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Bioscavengers are biopharmaceuticals that specifically react with toxicants. thus, enzymes reacting with poisonous esters can be used as bioscavengers for neutralization of toxic molecules before they reach physiological targets. Parenteral administration of bioscavengers is, therefore, intended for prophylaxis or pre-treatments, emergency and post-exposure treatments of intoxications. these enzymes can also be used for application on skin, mucosa and wounds as active components of topical skin protectants and decontamination solutions. Human butyrylcholinesterase is the first stoichiometric bioscavenger for safe and efficient prophylaxis of organophosphate poisoning. However, huge amounts of a costly enzyme are needed for protection. thus, the bioscavenger approach will be greatly improved by the use of catalytic bioscavengers. catalytic bioscavengers are enzymes capable of degrading toxic esters with a turnover. Suitable catalytic bioscavengers are engineered mutants of human enzymes. efficient mutants of human butyrylcholinesterase have been made that hydrolyze cocaine at a high rate. Mutants of human cholinesterases capable of hydrolyzing OPs have been made, but so far their activity is too low to be of medical interest. Human paraoxonase a promiscuous plasma enzyme is certainly the most promising phosphotriesterase. However, its biotechnology is still in its infancy. Other enzymes and proteins from blood and organs, and secondary biological targets of OPs and carbamates are potential bioscavengers, in particular serum albumin that reacts with OPs and self-reactivates. Lastly, non-human enzymes, phosphotriesterases and oxidases from various bacterial and eukaryotic sources could be used for external use against OP poisoning and for internal use after modifications for immunological compatibility.

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1 . THE BIOSCAVENGER CONCEPT Potter and Wadkins, 2006; Satoh and Hosokawa, 2006) in the enzyme systems located in skin, blood organs are involved in metabolism of drugs and xenobiotics is well known. the imnatural defences against endogenous and exogenous poisons. portance of plasma esterases in the inactivation of numerous Detoxification processes occur through different types of re-toxicants has been recognized, too. Lastly, there is growing actions, including oxidation, hydrolysis, and conjugation. the evidence that catalytic antibodies play also an efficient role role of liver, lung and kidney enzymes, cytochromes P450 in scavenging deleterious molecules and radicals (Belogurov (Brown et al., 2008), oxidases, transferases (Miners et al., et al., 2009). these multiple enzymes constitute cellular and 2006), amido-carboxylesterases (redinbo and Potter, 2005; circulating barriers that protect physiological machineries and systems against specific toxicants. Here we will examine endogenous and exogenous enzymes that react with poisonous carboxylic-, organophosphoryl- and carbamyl-esters. these enzymes act either as stoichiometric bioscavengers or catalytic bioscavengers. catalytic bioscavengers are biocatalysts capable of degrading poisonous compounds with a turnover. enzymes that are potential catalytic bioscavengers will be reviewed.

About the authors

Patrick Masson

Centre de Recherches du Service de Santé des Armées, Toxicology department; Institute of Structure Biology, Molecular Biophysics Laboratory

La Tronche, France; Grenoble, France; Grenoble, France

Daniel Rochu

Centre de Recherches du Service de Santé des Armées, Toxicology department; Bundeswehr Institute of Toxicology and Pharmacology

Munich, Germany


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