Antagonism of the lethal effects of paraoxon by carrier erythrocytes containing phosphotriesterase.
Annealed murine erythrocytes were employed as a carrier model to antagonize the toxic effects of organophosphorus agents. These resealed cells containing a recombinant phosphotriesterase provided striking protection against the lethal effect of paraoxon, an active metabolite of an agricultural pesticide, parathion. Phosphotriesterase hydrolyzes paraoxon to the less-toxic 4-nitrophenol and diethylphosphate. This enzyme was encapsulated into carrier erythrocytes by hypotonic dialysis with subsequent resealing and annealing. These carrier cells were administered to mice either alone or in combination with pralidoxime (2-PAM) and/or atropine. The recipient animals were subsequently challenged with paraoxon and a marked protection was noted. Protection of free enzyme and encapsulated enzyme was compared and the encapsulated enzyme was found to persist longer and possess much greater efficacy. Less serum cholinesterase inhibition also was observed with this enhanced protection. These results indicate that the erythrocyte carrier alone is quite effective in the antagonism of organophosphorus intoxication. Moreover, when these carrier cells were administered in combination with 2-PAM and/or atropine, a marked synergism was observed.
Pei
L
L
Department of Medical Pharmacology and Toxicology, Texas A&M University Health Science Center, College Station 77843-1114, USA.
Petrikovics
I
I
Way
J L
JL
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use; D043303:Aryldialkylphosphatase; D001285:Atropine / Q000494:pharmacology; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004338:Drug Combinations; D004912:Erythrocytes / Q000502:physiology*; D004950:Esterases / Q000378:metabolism / Q000494:pharmacology*; D007306:Insecticides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009026:Mortality; D010261:Paraoxon / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D013534:Survival; D013997:Time Factors
D000931:Antidotes; D004337:Drug Carriers; D004338:Drug Combinations; D007306:Insecticides; D011220:Pralidoxime Compounds; D001285:Atropine; D004950:Esterases; D002802:Cholinesterases; D043303:Aryldialkylphosphatase; C028797:pralidoxime; D010261:Paraoxon