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Paraoxonases in Inflammation, Infection, and Toxicology pp 47–60Cite as

The Toxicity of Mixtures of Specific Organophosphate Compounds is Modulated by Paraoxonase 1 Status

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 660))

Abstract

Most chemical exposures involve complex mixtures. The role of paraoxonase 1 (PON1) and the Q192R polymorphism in the detoxication of individual organophosphorous (OP) compounds has been well-established. The extent to which PON1 protects against a given OP is determined by its catalytic efficiency. We used a humanized transgenic mouse model of the Q192R polymorphism to demonstrate that PON1 modulates the toxicity of OP mixtures by altering the activity of another detoxication enzyme, carboxylesterase (CaE). Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of CaE, both in vitro and in vivo. We hypothesized that exposure of mice to these OPs would increase their sensitivity to the CaE substrate, malaoxon (MO), and that the degree of effect would vary among PON1 genotypes if the OP was a physiologically relevant PON1 substrate. When wild-type mice were exposed dermally to CPO, DZO, or PO and then, after 4 h, to different doses of MO, the toxicity of MO was increased compared to mice that received MO alone. The potentiation of MO toxicity by CPO and DZO was higher in PON1 knockout mice, which are less able to detoxify CPO or DZO. Potentiation by CPO was higher in Q192 mice than in R192 mice due to the decreased ability of PON1Q192 to detoxify CPO. Potentiation by DZO was similar in the Q192 and R192 mice, due to their equivalent effectiveness at detoxifying DZO. PO exposure resulted in equivalent potentiation of MO toxicity among all four genotypes. These results indicate that PON1 status modulates the ability of CaE to detoxicate OP compounds from specific mixed insecticide exposures. PON1 status can also impact the capacity to metabolize drugs or other CaE substrates following insecticide exposure.

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Acknowledgments

The authors thank Drs. Diana Shih, Aldons J. Lusis, and Aaron Tward for providing the PON1 –/– mice and the hPON1 Q192 and hPON1 R192 transgenic mice used in this study. This work was supported by National Institutes of Health Grants ES09883, ES04696, ES07033, and ES09601/EPA: RD-83170901. Figures were reproduced from a previously published manuscript (Jansen et al. 2009), with permission from Elsevier Press.

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Authors and Affiliations

  1. Department of Medicine (Div. of Medical Genetics) and Environmental Health and Occupational Medicine, University of Washington, Seattle, WA, USA

    Toby B. Cole

  2. Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA

    Karen Jansen, Sarah Park & Lucio G. Costa

  3. Department of Medicine (Div. of Medical Genetics) and Genome Sciences, Aberdeen Proving Ground, Aberdeen, MD, USA

    Sarah Park

  4. Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan Town, Taiwan

    Wan-Fen Li

  5. Department of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA

    Clement E. Furlong

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  1. Toby B. Cole
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  2. Karen Jansen
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  4. Wan-Fen Li
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  5. Clement E. Furlong
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  6. Lucio G. Costa
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Correspondence to Clement E. Furlong .

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  1. Division of Cardiology, University of California, Los Angeles, Le Conte Ave. 10833, Los Angeles, 90095-1679, U.S.A.

    Srinivasa T. Reddy

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Cole, T.B., Jansen, K., Park, S., Li, WF., Furlong, C.E., Costa, L.G. (2010). The Toxicity of Mixtures of Specific Organophosphate Compounds is Modulated by Paraoxonase 1 Status. In: Reddy, S. (eds) Paraoxonases in Inflammation, Infection, and Toxicology. Advances in Experimental Medicine and Biology, vol 660. Humana Press. https://doi.org/10.1007/978-1-60761-350-3_6

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