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Phosphotriesterase--a promising candidate for use in detoxification of organophosphates
K Tuovinen1, E Kaliste-Korhonen, F M Raushel
1Department of Physiology, University of Kuopio, Finland.
Abstract:
The effect of phosphotriesterase (PTE) on cholinesterase (ChE) activities was studied with exposures to different organophosphates in mice. Paraoxon (PO) (1.0 mg/kg, ip) almost totally inhibited serum ChE activity. This activity, however, recovered to the normal level within 24 hr. The PTE pretreatment (16.8 U/animal, 2.5 micrograms/10 g body wt, iv 10 min before the organophosphate) accelerated this reactivation. The same phenomenon was also seen in vitro. In vitro with human serum, there was only minimal reactivation of the inhibited ChE. PTE, however, reactivated it significantly. The PTE-pretreated mice (168 U/animal, 30 micrograms/10 g body wt, iv) tolerated even 50 mg/kg of PO without showing any remarkable signs of intoxication. In PTE-untreated animals, however, PO doses as low as 1.0 and 1.5 mg/kg caused severe signs of poisoning. PTE (16.8 U/animal, 4 micrograms/10 g body wt, iv) reduced the inhibition of brain and serum ChE activities after PO and diisopropyl fluorophosphate exposure. In sarin and soman intoxications, PTE decreased only slightly the inhibition of ChE activities. The results indicate that PTE pretreatment given iv prevents the inhibition of ChE activities after certain organophosphates and it also hastens the recovery of activities after PO poisoning.
Insights
Phosphotriesterase (PTE) enzyme pretreatment significantly accelerates the recovery of cholinesterase (ChE) activity inhibited by organophosphates like paraoxon. PTE also protects against organophosphate poisoning, enhancing survival rates in mice.
Area of Science:
- Biochemistry
- Toxicology
- Enzymology
Background:
- Cholinesterase (ChE) enzymes are crucial for nervous system function.
- Organophosphates are potent inhibitors of ChE, leading to toxicity.
- Developing effective antidotes for organophosphate poisoning is a critical medical need.
Purpose of the Study:
- To investigate the efficacy of phosphotriesterase (PTE) in reactivating and protecting against organophosphate-induced cholinesterase inhibition.
- To evaluate the protective effects of PTE against various organophosphate compounds in vivo and in vitro.
Main Methods:
- Mice were pretreated with PTE before exposure to organophosphates (Paraoxon, Sarin, Soman, DFP).
- Cholinesterase activity in serum and brain was measured.
- Survival rates and signs of intoxication were observed in PTE-treated and untreated animals.
- In vitro experiments assessed PTE's effect on human serum ChE inhibition.
Main Results:
- PTE pretreatment significantly accelerated the recovery of ChE activity inhibited by Paraoxon (PO).
- PTE-treated mice tolerated much higher doses of PO, showing reduced signs of intoxication and increased survival.
- PTE demonstrated significant in vitro reactivation of inhibited human serum ChE.
- PTE provided protection against PO and DFP but had a lesser effect against Sarin and Soman.
Conclusions:
- PTE is a promising therapeutic agent for organophosphate poisoning, particularly for Paraoxon.
- PTE pretreatment can prevent ChE inhibition and hasten recovery, offering significant protection.
- The effectiveness of PTE varies depending on the specific organophosphate agent.