Interspecies differences in enzymes reacting with organophosphates and their inhibition by paraoxon in vitro

Abstract

1 Inhibition of cholinesterases (ChE) and carboxyles terases (CaE) by paraoxon (Px) was studied in vitro in the serum, liver, lung and muscle of mouse, guinea pig, rabbit and man (serum only). Moreover, the role ofPx hydrolyzing enzyme (Pxase) in the detoxification of Px was studied by inhibiting its activity with EDTA.

2 The ChE and CaE activities as well as their sensitivity to Px varied in different tissues and species. The ChEs were more sensitive than CaEs to Px except in the liver. The CaE activity in human and rabbit sera was low and resistant to Px, indicating that it may have a minor importance for the binding of Px.

3 The Px-inhibited ChEs were spontaneously reactivated in the mouse and rabbit sera during 24 h. In mouse, also the CaE activity was recovered. The presence of EDTA in the incubation medium prevented this reactivation indicating that Pxase takes part in the reactivation process.

4 In rabbit, the serum Pxase activity was very high suggesting a good Px detoxifying capacity of the rabbit serum.

5 The results show that amounts and sensitivities of esterases to OPs in rodents may markedly differ from that in man. Possible species-related differences in the affinity of ChEs and CaEs for OPs and the OP hydrolyzing activity should be taken into the con sideration, when animal data are extrapolated to man.

Keywords

paraoxon cholinesterase carboxylesterase paraoxo nase different species different tissues

Get full access to this article

View all access options for this article.

References

Tafuri J. , Roberts J. Organophosphate poisoning. Annals of Emergency Medicine 1987; 16: 193- 202.

Koelle GB et al. Selective, near-total, irreversible inactivation of peripheral pseudocholinesterase and acetylcholine in cats in vivo. Biochemical Pharmacology 1974; 23: 175-88.

Junge W. , Krisch K. The carboxylesterases/ amidases of mammalian liver and their possible significance . CRC Critical Reviews of Toxicology 1975; 3: 371-434.

Maxwell DM et al. The effects of blood flow and detoxification on in vivo cholinesterase inhibition by soman in rats. Toxicology and Applied Pharmacology 1987; 88: 66-76.

Clement JG Importance of aliesterase as a detoxification mechanism for soman (pinacolyl methylphosphonofluoridate) in mice. Biochemical Pharmacology 1984; 33: 3807-11.

Maxwell DM The specificity of carboxylesterase protection against the toxicity of organophosphorus compounds. Toxicology and Applied Pharmacology 1992; 114: 306-12.

Maxwell DM , Brecht KM , O'Neill BL The effect of carboxylesterase inhibition on interspecies differences in soman toxicity. Toxicology Letters 1987; 39: 35-42.

Aldridge WN Serum esterases. Biochemical Journal 1953; 53: 110-24.

Butler EG , Eckerson HW , La Du BN Paraoxon hydrolysis vs. covalent binding in the elimination of paraoxon in the rabbit. Drug Metabolism and Disposition 1985; 13: 640-5.

10.

Traverso R. , Moretto A. , Lotti M. Human serum A-esterases, Hydrolysis of O,O-dimethyl-2,2-dichlorovinyl phosphate. Biochemical Pharmacology 1989; 38: 671-6.

11.

Gil F. et al. Differences in the kinetic properties, effect of calcium and sensitivity to inhibitors of paraoxon hydrolase activity in rat plasma and microsomal fraction from rat liver. Biochemical Pharmacology 1994; 48: 1559-68.

12.

Ellman GL , Courne KD , Andres V. Jr , Featherstone RM A new and rapid colorimetric determination of acetylcholinesterase activity . Biochemical Pharmacology 1961; 7: 88-95.

13.

Zemaitis MA , Green FE Impairment of hepatic microsomal and plasma esterases of the rat by disulfiram and diethyldithiocarbamate. Biochemical Pharmacology 1976; 25: 453-9.

14.

Tuovinen K. , Kaliste-Korhonen E. , Raushel FM , Hänninen O. Phosphotriesterase-a promising candidate for use in detoxification of organophosphates . Fundamental and Applied Toxicology 1994; 23: 578-4.

15.

Siegel S. Nonparametric statistics for the behavioral sciences 2nd edition, McGraw-Hill Book Company. New York, 1988.

16.

Gearhart JM et al. Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters . Environmental Health Perspectives 1994; 102(Suppl 11): 51- 60.

17.

Chambers JE , Carr RL Inhibition patterns of brain acetylcholinesterase and hepatic and plasma aliesterases following exposures to three phusphurothionate insecticides and their oxons in rats. Fundamental and Applied Toxicology 1993; 21: 111- 9.

18.

Jokanovic M. , Kosanovic M. , Maksimovic M. Interaction of organophosphorus compounds with carboxylesterases in the rat. Archives of Toxicology 1996; 70: 444-50.

19.

Evans RT Cholinesterase phenotyping: clinical aspects and laboratory applications , CRC Critical Reviews in Clinical Laboratory Sciences 1986; 23: 35-64.

20.

Schwarz M. et al. Successive organophosphate inhibition and oxide reactivation reveals distinct responses of recombinant cholinesterase variants. Molecular Brain Research 1995; 31: 101-10.

21.

Geldmacher-v. Mallinckrodt M. , Diepgen TL Human serum paraoxonase-polymorphism, specificity, classification. In: Reiner E, Aldridge WN and Hoskin FCG (eds.), Enzymes hydrolyzing organophosphorus compounds Ellis Horwood Limited, West Sussex, England 1989. pp. 15-29.

22.

Matsubara T. , Horikoshi I. Sponatenous reactivation of fenitro-oxon-inhibited plasma cholinesterase in various mammals. Journal of Pharmaceutical Dynamics 1982; 5: 155-61.

23.

Tuovinen K. , Kaliste-Korhonen E. , Raushel FM , Hänninen O. Protection of organophosphate-inactivated esterases with phosphotriesterase. Fundamental and Applied Toxicology 1996; 31: in press.