Abstract
Many organophosphorus compounds (OPs) are potent cholinesterase inhibitors, accounting for their use as insecticides and, unfortunately, also as nerve agents. Each year there are approximately 3 million pesticide poisonings world-wide resulting in 220,00 deaths1–2. In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg of diazinon and 1.23 million kg of ethyl parathion manufactured in the USA (data supplied by the USEPA). In addition to exposure risks during pesticide manufacturing, distribution and use, there are risks associated with the major international effort aimed at destroying the arsenals of nerve agents, including soman and sarin. The United States has pledged to destroy approximately 25,000 tons of chemical agents by the end of the decade3. The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors4 by cytochrome P-450 systems5. The resulting toxic oxon forms can be hydrolysed by PON1, which also hydrolyses the nerve agents soman and sarin6 (Fig. 1). PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme7–9. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly, while the Gln192 (Q191) isoform hydrolyses paraoxon slowly6,10. Both isoforms hydrolyse chlorpyrifos-oxon8,9 and phenylacetate6,7,9 at approximately the same rate. The role of PON1 in OP detoxication is physiologically significant11–15. Injected PON1 protects against OP poisoning in rodent model systems12–15 and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values8,11,16. We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OR extending earlier studies on this system. We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective.
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References
World Health Organization. Informal consultation on planning strategy for the prevention of pesticide poisoning Geneva. 25–29 November 1985. WHO/VBC/86. 926. (Geneva: WHO, 1988).
World Health Organization. Public health impact of pesticides used in agriculture. (Geneva: WHO, 1990).
U.S. Congress, Office of Technology Assessment. Disposal of Chemical Weapons: Alternative Technologies — Background Paper, OTA-BP-0-95 (Washington, DC: U.S. Government Printing Office, June 1992).
Tafuri, J. & Roberts, J. Organophosphate poisoning. Ann. Emerg. Med. 16, 193–202 (1987).
Murphy, S.D. in Toxicology: The Basic Science of Poisons. (eds Doull, J., Klassen, C., & Amdur, M. ) 357–408 (Macmillan, New York, 1980).
Smolen, A., Eckerson, H.W., Gan, K.N., Hailat, N. & LaDu, B.N. Characteristics of the genetically determined allozymic forms of human serum paraoxonase/arylesterase. Drug Metab. Dispos. 19, 107–112 (1991).
LaDu, B.N., Piko, J.I., Eckerson, H.W., Vincent-Viry, M. & Seist, G. An improved method for phenotyping individuals for the human serum paraoxonase arylesterase polymorphism. Ann. Biol. Clin. 44, 369–372 (1986).
Furlong, C.E., Richter, R.J., Seidel, S.L., Costa, L.G. & Motulsky, A.G. Spectrophotometric assays for the enzymatic hydrolysis of the active metabolites of chlorpyrifos and parathion by plasma paraoxonase/ arylesterase. Analyt. Biochem. 180, 242–247 (1989).
Furlong, C.E., Richter, R.J., Seidel, S.L., Costa, L.G. & Motulsky, A.G. Role of genetic polymorphism of human plasma paraoxonase/arylesterase in hydrolysis of the insecticide metabolites chlorpyrifos oxon and paraoxon. Am. J. Hum. Genet. 43, 230–238 (1988).
Humbert, R. et al. The molecular basis of the human serum paraoxonase activity polymorphism. Nature Genet. 3, 73–76 (1993).
Costa, L.G. et al. Species differences in serum paraoxonase activity correlate with sensitivity to paraoxon toxicity. Toxicology of Pesticides: Experimental, Clinical and Regulatory Aspects, in NATO ASI Series. Vol. H13 (Eds, L. G. Costa, et al.) 263–266 (Springer-Vertag, Berlin 1987).
Costa, L.G. et al. Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats. Tox. Appl. Pharmac. 103, 66–76 (1990).
Li, W.-F., Costa, L.G. & Furlong, C.E. Serum paraoxonase status: a major factor in determining resistance to organophosphates. J. Tox. Envir. Hlth 40, 337–346 (1993).
Li, W.-F., Furlong, C.E. & Costa, L.G. Paraoxonase protects against chlorpyrifos toxitity in mice. Tox. Lett. 76, 219–226 (1995).
Main, A.R. The role of A-esterase in the acute toxicity of paraoxon, TEPP, and parathion. Can. J. Biochem. 34, 197–216 (1956).
McCollister, S.B., Kociba, R.J., Humiston, C.G. & McCollister, D.D. Studies on the acute and long-term oral toxicity of chlorpyrifos (0,0-diethyl-0 (3,5,6-trichloro-2-pyridyl) phosphorothioate). Food Cosmet. Tox. 12, 45–61 (1974).
Zech, R. & Zurcher, K. Organophosphate splitting enzymes in different mammals. Comp. Biochem. Physiol. 48B, 427–433 (1974).
Geldmacher-von, Mallinckrodt M. & Dlepgen, T.L. The human serum paraoxonase-polymorphism and specificity. Toxicol. Environ. Chem. 18, 79–196 (1988).
Mueller, R.F. et al. Plasma paraoxonase polymorphism: a new enzyme assay, population, family, biochemical and linkage studies. Am. J. Hum. Genet. 35, 393–408 (1983).
Benke, G.M. & Murphy, S.D. The influence of age on the toxicity and metabolism of methyl parathion and parathion in male and female rats. Tox. Appl. Pharmac. 31, 254–269 (1975).
Burnett, W.T. & Chambers, J.E. Age-related toxicity of the insecticides parathion and chlorpyrifos. Toxicologist 14, 390 (1994).
Watson, A.D. et al. Protective effect of high density lipoprotein associated paraoxonase: Inhibition of the biological activity of minimally oxidized low density lipoprotein. J. Clin. Invest. 96, 2882–2891 (1995).
Ruiz, J. et al. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet 346, 869–872 (1995).
Serrato, M. & Marian, A.J. A variant of human paraoxonase/arylesterase (HUMPON1A) gene is a risk factor for coronary artery disease. J. Clin. Invest. 96, 3005–3008 (1995).
Hama, H., Iwata, T., Miyata, T. & Saito, T. Some properties of acetylcholinesterases partially purified from susceptible and resistant green rice leafhoppers, Nephotettix cincticeps Uhler (Hemiptera: Deltocephalidae). Appl. Ent. Zool. 15, 249–261 (1980).
St. Clair, M.H. et al. Resistance to ddl and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 253, 1557–1559 (1991).
Amzten, C.J., Pfister, K. & Steinback, K. The mechanism of chloroplast triazine resistance: alterations in the site of herbicide action, in Herbicide Resistance in Plants (eds LeBaron, H.M. & Gressel, J. ) 194–195 (John Wiley & Sons, New York, 1982).
Kitchen, G.J., Masters, C.J. & Winzor, D.J. Effects of lipid removal on the molecular size and kinetic properties of bovine plasma arylesterase. Biochem. J. 135, 93–99 (1973).
Gomaa, H.M., Suffet, I.H. & Faust, S.D. Kinetics of hydrolysis of diazinon and diazoxon. Residue Rev. 29, 171–190 (1969).
Shishido, T. & Fukami, J.-I. Enzymatic hydrolysis of diazoxon by rat tissue homogenates. Pestic. Biochem. Physiol. 2, 39–50 (1972).
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Davies, H., Richter, R., Keifer, M. et al. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet 14, 334–336 (1996). https://doi.org/10.1038/ng1196-334
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DOI: https://doi.org/10.1038/ng1196-334