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Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Nature volume 394, pages 284–287 (1998)Cite this article

Abstract

Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos1,2,3. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs)4,5,6,7,8. To study the role of PON1 in vivo, we created PON1 -knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1 -knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1 -null mice were more susceptible to atherosclerosis than their wild-type littermates.

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Figure 1: Targeted disruption of the PON1 gene.
Figure 2: PON1 null mice are more sensitive to the toxic effects of chlorpyrifos oxon and chlorpyrifos.
Figure 3: PON1 null mice are susceptible to lipoprotein oxidation and atherosclerosis.

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References

  1. Murphy, S. D. in Toxicology: The Basic Science of Poisons(eds Doull, J., Klassen, C. & Amdur, M.) 357–408 (Macmillan, New York, (1980)).

    Google Scholar 

  2. Tafuri, J. & Roberts, J. Organophosphate poisoning. Ann. Emerg. Med. 16, 193–202 (1987).

    Article  CAS  Google Scholar 

  3. Smolen, A., Eckerson, H. W., Gan, K. N., Hailat, N. & La Du, B. N. Characteristics of the genetically determined allozymic forms of human serum paraoxonase/arylesterase. Drug Metab. Dispos. 19, 107–112 (1991).

    CAS  PubMed  Google Scholar 

  4. Mackness, M. I., Arrol, S. & Durrington, P. N. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 286, 152–154 (1991).

    Article  CAS  Google Scholar 

  5. Watson, A. D. et al. Protective effect of HDL associated paraoxonase-inhibition of the biological activity of minimally oxidized low density lipoprotein. J. Clin. Invest. 96, 2882–2891 (1995).

    Article  CAS  Google Scholar 

  6. Shih, D. M. et al. Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J. Clin. Invest. 97, 1630–1639 (1996).

    Article  CAS  Google Scholar 

  7. Mackness, M. I., Mackness, B., Durrington, P. N., Connelly, P. W. & Hegele, R. A. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr. Opin Lipidol. 7, 69–76 (1996).

    Article  CAS  Google Scholar 

  8. Heinecke, J. W. & Lusis, A. J. Paraoxonase-gene polymorphisms associated with coronary heart disease: Support for the oxidative damage hypothesis? Am. J. Hum. Genet. 62, 20–24 ((1998)).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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).

    CAS  Google Scholar 

  11. Li, W.-F., Costa, L. G. & Furlong, C. E. Paraoxonase protects against chlorpyrifos toxicity in mice. Tox. Lett. 76, 219–226 (1995).

    Article  CAS  Google Scholar 

  12. Humbert, R. et al. The molecular basis of the human serum paraoxonase activity polymorphism. Nature Genet. 3, 73–76 (1993).

    Article  ADS  CAS  Google Scholar 

  13. Davies, H. G. et al. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nature Genet. 14, 334–336 (1996).

    Article  CAS  Google Scholar 

  14. Navab, M. et al. Monocyte transmigration induced by modification of low density lipoprotein in coculture of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J. Clin. Invest. 88, 2039–2046 (1991).

    Article  CAS  Google Scholar 

  15. Navab, M. et al. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J. Clin. Invest. 99, 2005–2019 (1997).

    Article  CAS  Google Scholar 

  16. Watson, A. D. et al. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J. Clin. Invest. 95, 774–782 (1995).

    Article  CAS  Google Scholar 

  17. Mehrabian, M. et al. Influence of the apoA-II gene locus on HDL levels and fatty streak development in mice. Arterioscler. Thromb. 13, 1–10 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by an NIH grant (to A.J.L., A.M.F. and M.N.), an NIEHS grant (to C.E.F.) and an American Heart Association Grant-in-Aid awarded by Greater Los Angeles Affiliate (to D.M.S.). We thank H. Cheroutre and K. Williams of UCLA Transgenic Core Facility for blastocyst injections; W. R. Clark and K. M. Lyons for advice in gene targeting work; S. Charugundla for lipid assays; G. P. Hough for MCP-1 assay; and X.-P. Wang and Y.-S. Shi for aortic lesion analysis.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, 47-123 CHS, UCLA School of Medicine, Los Angeles, 90095, California, USA

    Diana M. Shih, Lingjie Gu, Yu-Rong Xia, Mohamad Navab, Susan Hama, Lawrence W. Castellani, Alan M. Fogelman & Aldons J. Lusis

  2. Department of Microbiology and Molecular Genetics, Molecular Biology Institute, UCLA, Los Angeles, 90095, California, USA

    Diana M. Shih, Lingjie Gu, Yu-Rong Xia, Lawrence W. Castellani & Aldons J. Lusis

  3. Department of Environmental Health, University of Washington, Seattle, 98195, Washington, USA

    Wan-Fen Li & Lucio G. Costa

  4. Departments of Medicine and Genetics, University of Washington, Seattle, 98195, Washington, USA

    Clement E. Furlong

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  1. Diana M. Shih
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Correspondence to Aldons J. Lusis.

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Shih, D., Gu, L., Xia, YR. et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394, 284–287 (1998). https://doi.org/10.1038/28406

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