Abstract
Human paraoxonase 1 (PON1) has broad substrate specificity and has been shown to protect against exposure to some organophosphorus (OP) insecticides due to its ability to hydrolyze toxic metabolites of some organophosphorothioate insecticides. PON1 status has been shown to be important in protecting against vascular disease, presumably due to the not-as-yet fully characterized role of the three PON proteins in modulating oxidative stress. More recently, all three PONs (1, 2, and 3) have been shown to inactivate the quorum sensing factor N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) of Pseudomonas. Expression of human PON1 in Drosophila demonstrated the importance of PON1 in resistance to Pseudomonas infection. Many studies have examined only DNA single nucleotide polymorphisms as possible risk factors for disease or exposures. For all of the known functions of PON1, the level of PON1 enzyme is important and, in some cases, also the Q192R polymorphism. A simple high throughput two-substrate assay/analysis, plotting rates of diazoxon hydrolysis vs. paraoxon hydrolysis, provided both PON1 levels and functional Q192R phenotype/genotype. We have developed a new two-substrate assay/analysis protocol that provides PON1 status without use of toxic OP substrates. Factors were determined for inter-converting rates of hydrolysis of different substrates.
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References
Brophy VH, Jarvik GP, Furlong CE (2002) PON1 Polymorphisms. In: Costa LG, Furlong CE (eds.). Paraoxonase (PON1) in Health and Disease: Basic and Clinical Aspects. Boston: Kluwer Academic Press. 53-77
Costa LG, Vitalone A, Cole TB and Furlong CE (2005) Modulation of paraoxonase (PON1) activity. Biochem Pharmacol 69:541–550
Chun CK, Ozer EA, Welsh MJ, Zabner J, Greenberg EP (2004) Inactivation of a Pseudomonas aeruginosa quorum sensing signal by human airway epithelia. Proc Natl Acad Sci USA 101:3587–3590
Cole TB, Walter BJ, Shih DM, Tward AD, Lusis AJ, Timchalk C, Richter RJ, Costa LG, Furlong CE (2005) Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenet Genomics 15:589–598
Costa LG, McDonald BE, Murphy SD, Omenn GS, Richter RJ, Motulsky AG, Furlong CE (1990) Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats. Toxicol Appl Pharmacol 103:66–76
Davies H, Richter RJ, Keifer M, Broomfield C, Sowalla J, Furlong CE (1996) The human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nature Genet 14:334–336
Deakin S, Leviev I, Brulhart-Meynet M-C, James RW (2003) Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position −107, implicating the Sp1 transcription factor. Biochem J 372:643–649
Deakin SP, James RW (2004) Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci (Lond.) 107:435–447
Eckerson HW, Wyte CM, La Du BN (1983) The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet 35:1126–1138
Furlong CE, Richter RJ, Li W-F, Brophy VH, Carlson C, Meider M, Nickerson D, Costa LG, Ranchalis J, Lusis AJ, Shih DM, Tward A, Jarvik GP (2008) The functional consequences of polymorphisms in the human PON1 gene. In: Mackness B, Mackness M, Aviram M, Paragh G (eds). The Paraoxonases: Their Role in Disease, Development and Xenobiotic Metabolism. Dordrecht, The Netherlands: Springer. 267–281
Furlong C, Holland N, Richter R, Bradman A, Ho A, Eskenazi B (2006) PON1 status of farmworker mothers and children as a predictor of organophosphate sensitivity. Pharmacogenet Genomics 16:183–190
James RW. (2006) A long and winding road: defining the biological role and clinical importance of paraoxonases. Clin Chem Lab Med 44:1052–1059
Jarvik GP, Rozek LS, Brophy VH, Hatsukami TS, Richter RJ, Schellenberg GD, Furlong CE (2000) Paraoxonase phenotype is a better predictor of vascular disease than PON1192 or PON155 genotype. Atheroscler Thromb Vasc Biol 20:2442–2447
Jarvik GP, Jampsa R, Richter RJ, Carlson C, Rieder M, Nickerson D, Furlong CE (2003) Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics 13:291–295
La Du BN (2003) Future studies of low-activity PON1 phenotype subjects may reveal how PON1 protects against cardiovascular disease, Arterioscler Thromb Vasc Biol 23:1317–1318
Lawlor DA, Day IN, Gaunt TR, Hinks LJ, Briggs PJ, Kiessling M, Timpson N, Smith GD, Ebrahim S (2004) The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women’s Heart and Health cohort study and a meta-analysis. BMC Genet 5:17
Li W-F, Costa LG, Furlong CE (1993) Serum paraoxonase status: a major factor in determining resistance to organophosphates. J Toxicol Environ Health 40:337–346
Li W-F, Furlong CE, Costa LG (1995) Paraoxonase protects against chlorpyrifos toxicity in mice. Toxicol Lett 76:219–226
Li W-F, Costa LG, Richter RJ, Hagen T, Shih DM, Tward A, Lusis AJ, Furlong CE (2000) Catalytic efficiency determines the in vivo efficacy of PON1 for detoxifying organophosphates. Pharmacogenetics 10:767–780
Mackness B, Davies GK, Turkie W, Lee E, Roberts DH, Hill E, Roberts C, Durrington PN, Mackness MI (2001) Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol 21:1451–1457
Ozer EA, Pezzulo A, Shih DM, Chun C, Furlong C, Lusis AJ, Greenberg EP, Zabner J (2005) Human and murine Paraoxonase 1 are host modulators of P. aeruginosa quorum-sensing. FEMS Microbiol Lett 253:29–37
Richter RJ, Furlong CE (1999) Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenetics 9:745–753
Richter RJ, Jarvik GP, Furlong CE (2008) Determination of paraoxonase 1 status without the use of toxic organophosphate substrates. Circ Cardiovasc Genet 1:147–152 DOI: 10.1161/CIRCGENETICS.108.811638
Richter RJ, Jarvik GP, Furlong CE (2009) Paraoxonase 1 (PON1) status and substrate hydrolysis. Toxicol Appl Pharmacol 235:1–9
Shih DM, Gu L, Xia Y-R, Navab M, Li W-F, Hama S, Castellani LW, Furlong CE, Costa, LG, Fogelman AM, Lusis AJ (1998) Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394:284–287
Stoltz DA, Ozer EA, Taft PJ, Barry M, Liu L, Kiss PJ, Moninger TO, Parsek MR, Zabner J (2008) Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1. J Clin Invest 118:3123–3131 doi:10.1172/JCI35147
Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh J (2004) Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Lancet 363:689–695.
Acknowledgments
This work was supported by grants from the National Institute of Environmental Health Sciences ES09883, ES04696, ES07033, ES09601 – EPA: RD-83170901-OE and the National Heart, Lung, and Blood Institute, HL67406 and HL074366.
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Richter, R.J., Jarvik, G.P., Furlong, C.E. (2010). Paraoxonase 1 Status as a Risk Factor for Disease or Exposure. 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_4
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DOI: https://doi.org/10.1007/978-1-60761-350-3_4
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