Antagonism of paraoxon intoxication by recombinant phosphotriesterase encapsulated within sterically stabilized liposomes.
This investigation effort is focused on increasing organophosphate (OP) degradation by phosphotriesterase to antagonize OP intoxication. For these studies, sterically stabilized liposomes encapsulating recombinant phosphotriesterase were employed. This enzyme was obtained from Flavobacterium sp. and was expressed in Escherichia coli. It has a broad substrate specificity, which includes parathion, paraoxon, soman, sarin, diisopropylfluorophosphate, and other organophosphorous compounds. Paraoxon is rapidly hydrolyzed by phosphotriesterase to the less toxic 4-nitrophenol and diethylphosphate. This enzyme was isolated and purified over 1600-fold and subsequently encapsulated within sterically stabilized liposomes (SL). The properties of this encapsulated phosphotriesterase were investigated. When these liposomes containing phosphotriesterase were incubated with paraoxon, it readily degraded the paraoxon. Hydrolysis of paraoxon did not occur when these sterically stabilized liposomes contained no phosphotriesterase. These sterically stabilized liposomes (SL) containing phosphotriesterases (SL)* were employed as a carrier model to antagonize the toxic effects of paraoxon by hydrolyzing it to the less toxic 4-nitrophenol and diethylphosphate. This enzyme-SL complex (SL)* was administered intravenously to mice either alone or in combination with pralidoxime (2-PAM) and/or atropine intraperitoneally. These results indicate that this carrier model system provides a striking enhanced protective effects against the lethal effects of paraoxon. Moreover when these carrier liposomes were administered with 2-PAM and/or atropine, a dramatic enhanced protection was observed.
Petrikovics
I
I
College of Medicine, Texas A&M University, College Station, Texas, 77843-1114, USA.
Hong
K
K
Omburo
G
G
Hu
Q Z
QZ
Pei
L
L
McGuinn
W D
WD
Sylvester
D
D
Tamulinas
C
C
Papahadjopoulos
D
D
Jaszberenyi
J C
JC
Way
J L
JL
D000818:Animals; D043303:Aryldialkylphosphatase; D004337:Drug Carriers; D004950:Esterases / Q000008:administration & dosage*; D007306:Insecticides / Q000506:poisoning*; D007526:Isoelectric Point; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010261:Paraoxon / Q000037:antagonists & inhibitors / Q000506:poisoning*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage
D004337:Drug Carriers; D007306:Insecticides; D008081:Liposomes; D011220:Pralidoxime Compounds; D011994:Recombinant Proteins; D004950:Esterases; D043303:Aryldialkylphosphatase; C028797:pralidoxime; D010261:Paraoxon