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Toxicological Sciences 57, 16-21 (2000)
Copyright © 2000 by the Society of Toxicology

Biotransformation and Toxicokinetics

Long Circulating Liposomes Encapsulating Organophosphorus Acid Anhydrolase in Diisopropylfluorophosphate Antagonism

I. Petrikovics*, T.-C. Cheng{dagger}, D. Papahadjopoulos{ddagger}, K. Hong{ddagger}, R. Yin{dagger}, J. J. DeFrank{ddagger}, J. Jaing*, Z. H. Song*, W. D. McGuinn*, D. Sylvester*, L. Pei*, J. Madec*, C. Tamulinas*, J. C. Jaszberenyi§, T. Barcza§ and J. L. Way*,1

* Department of Medical Pharmacology and Toxicology, Texas A&M University, College of Medicine, College Station, Texas 77843-1114; {dagger} U.S. Army Chemical and Biological Defense Agency, Aberdeen Proving Ground, Maryland 21010-5423; {ddagger} Liposomal Research Laboratory, California Medical Center Research Institute, San Francisco, California 94115; and § Department of Organic Chemical Technology, Research Group of the Hungarian Academy of Sciences, Technical University of Budapest, Budapest, Hungary H-1521

These studies are focused on antagonizing organophosphorous (OP) intoxications by a new conceptual approach using recombinant enzymes encapsulated within sterically stabilized liposomes to enhance diisopropylfluorophosphate (DFP) degradation. The OP hydrolyzing enzyme, organophosphorous acid anhydrolase (OPAA), encapsulated within the liposomes, was employed either alone or in combination with pralidoxime (2-PAM) and/or atropine. The recombinant OPAA enzyme, from the Alteromonas strain JD6, has high substrate specificity toward a wide range of OP compounds, e.g., DFP, soman, and sarin. The rate of DFP hydrolysis by liposomes containing OPAA (SL)* was measured by determining the changes in fluoride-ion concentration using a fluoride ion-selective electrode. This enzyme carrier system serves as a biodegradable protective environment for the OP-metabolizing enzyme (OPAA), resulting in an enhanced antidotal protection against the lethal effects of DFP. Free OPAA alone showed some antidotal protection; however, the protection with 2-PAM and/or atropine was greatly enhanced when combined with (SL)*.

Key Words: phosphotriesterase; OPA anhydrase; OPAA; DFP antagonism; sterically stabilized liposomes; OP hydrolase (OPH); organophosphorus antagonism; stealth liposomes; long circulating liposomes.


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