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The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin

Nature Genetics volume 14, pages 334–336 (1996)Cite this article

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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Authors and Affiliations

  1. Departments of Genetics, University of Washington, Seattle, Washington, 98195-7360, USA

    Holly G. Davies, Rebecca J. Richter & Clement E. Furlong

  2. Medicine-Division of Medical Genetics, University of Washington, Seattle, Washington, 98195-7360, USA

    Rebecca J. Richter & Clement E. Furlong

  3. Occupational & Environmental Medicine, University of Washington, Seattle, Washington, 98195-7360, USA

    Matthew Keifer

  4. USAMRICD, Aberdeen, Maryland, USA

    Clarence A. Broomfield & Jason Sowalla

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  1. Holly G. Davies
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Correspondence to Clement E. Furlong.

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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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