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Gene Review

PON1  -  paraoxonase 1

Homo sapiens

Synonyms: A-esterase 1, Aromatic esterase 1, ESA, K-45, MVCD5, ...
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Disease relevance of PON1


Psychiatry related information on PON1


High impact information on PON1

  • 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 OP, extending earlier studies on this system [10].
  • 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 [10].
  • Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values [10].
  • 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 inhibitors by cytochrome P-450 systems [10].
  • A genetic polymorphism of paraoxonase (PON) activity which determines high versus low paraoxon hydrolysis in human populations, may determine sensitivity to parathion poisoning [11].

Chemical compound and disease context of PON1


Biological context of PON1

  • However, among white women, when data were stratified by the number of diseased vessels, the frequency of the PON1 codon 192 Arg/Arg genotype was significantly higher in the group with three-vessel disease than in the other groups (those with one-vessel and two-vessel disease) combined (17.02% vs. 4.58%; P=.0066) [15].
  • We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD [16].
  • PON1 activity and mass are both reduced in cardiovascular diseases and the hypocholesterolemic drugs, statins, increase serum PON1 activity (by reducing oxidative stress, or by upregulating hepatic PON1 expression) [17].
  • In contrast, a serine esterase inhibitor abolished phospholipase activity even though PON1 has no active-site serine residues [18].
  • With regard to the PON1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied [19].

Anatomical context of PON1


Associations of PON1 with chemical compounds


Physical interactions of PON1

  • LCAT has been reported to be involved in reverse-cholesterol transport and PON to be preventive for lipid peroxidation of low-density lipoprotein in vitro [23].
  • Paraoxonase (PON) is transported primarily on apolipoprotein A-I (apoA-I) -containing high-density lipoprotein (HDL) and is thought to protect against early atherogenic events including low-density lipoprotein (LDL) oxidation and monocyte migration [24].

Regulatory relationships of PON1

  • Apolipoprotein A-I promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by paraoxonase (PON-1) during high density lipoprotein oxidation with a peroxynitrite donor [22].
  • The PON1 promoter polymorphism C(-108)T may influence insulin sensitivity by modulating serum antioxidant capacity [25].
  • NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP [26].
  • Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01) [27].
  • PON1 attenuates the ox-LDL induced MCP-1 production by endothelial cells [28].

Other interactions of PON1

  • Three polymorphisms in the PON1 (Leu55Met and Gln192Arg) and PON2 (Ser311Cys) genes have been shown to be associated with the risk of CAD in several European or European-derived populations [15].
  • Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization [29].
  • However, the effect of apolipoprotein A-I and paraoxonase-1 (PON-1) on phosphatidylcholine oxidation products has not been identified [22].
  • METHODS: Polymorphisms of three xenobiotic genes (CYP17, GSTP1, PON1) were characterized in 384 patients with untreated PCa and 360 age-matched control patients with benign prostatic hyperplasia (BPH) [30].
  • The odds ratios (OR) adjusted for age, gender, and APOE polymorphism by logistic regression analysis highlighted that in AD the PON1 RR genotype was significantly protective (OR=0.41, 95% CI=0.19-0.90; P=0.025), whereas in CAD it appeared to be a significant risk factor (OR=5.11, 95% CI=1.09-23.9; P=0.038) limited to younger patients [5].

Analytical, diagnostic and therapeutic context of PON1

  • The SOD2 gene was screened by denaturing reversed-phase HPLC, and the PON1 (Q192R and M55L) and PON2 (S311C) polymorphisms were analyzed by PCR amplification followed by digestion with restriction endonucleases [4].
  • RESULTS: PON1 activity was highest in the more dense HDL(3) and VHDL fractions where PON1 was not dissociated from the particles during centrifugation [31].
  • The PON1-55 and PON1-192 polymorphisms affected PON1 activity in the way described in a previous study of a control group and subjects with type II diabetes [32].
  • Using site-directed mutagenesis and expression in human 293T cells, we have identified the following eight amino acids as being essential to PON1 activity: W280, H114, H133, H154, H242, H284, E52 and D53 [33].
  • Case-control studies of PON1 activity and coronary heart disease (CHD) have shown a clear association between CHD and low serum PON1 activity [34].


  1. Paraoxonase and coronary heart disease. Mackness, M.I., Mackness, B., Durrington, P.N. Atherosclerosis. Supplements. (2002) [Pubmed]
  2. TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease. Carlson, C.S., Heagerty, P.J., Hatsukami, T.S., Richter, R.J., Ranchalis, J., Lewis, J., Bacus, T.J., McKinstry, L.A., Schellenberg, G.D., Rieder, M., Nickerson, D., Furlong, C.E., Chait, A., Jarvik, G.P. J. Lipid Res. (2006) [Pubmed]
  3. Thematic review series: The immune system and atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? Chait, A., Han, C.Y., Oram, J.F., Heinecke, J.W. J. Lipid Res. (2005) [Pubmed]
  4. Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss. Fortunato, G., Marciano, E., Zarrilli, F., Mazzaccara, C., Intrieri, M., Calcagno, G., Vitale, D.F., La Manna, P., Saulino, C., Marcelli, V., Sacchetti, L. Clin. Chem. (2004) [Pubmed]
  5. Different pattern of association of paraoxonase Gln192-->Arg polymorphism with sporadic late-onset Alzheimer's disease and coronary artery disease. Scacchi, R., Gambina, G., Martini, M.C., Broggio, E., Vilardo, T., Corbo, R.M. Neurosci. Lett. (2003) [Pubmed]
  6. Association of paraoxonase-1 M55L genotype and alcohol consumption with coronary atherosclerosis: the Helsinki Sudden Death Study. Rontu, R., Lehtimäki, T., Ilveskoski, E., Mikkelsson, J., Kajander, O., Goebeler, S., Perola, M., Penttilä, A., Karhunen, P.J. Pharmacogenetics (2004) [Pubmed]
  7. Dietary modifications and gene polymorphisms alter serum paraoxonase activity in healthy women. Rantala, M., Silaste, M.L., Tuominen, A., Kaikkonen, J., Salonen, J.T., Alfthan, G., Aro, A., Kesäniemi, Y.A. J. Nutr. (2002) [Pubmed]
  8. Paraoxonase 1 192/55 gene polymorphisms in Alzheimer's disease. Dantoine, T.F., Drouet, M., Debord, J., Merle, L., Cogne, M., Charmes, J.P. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  9. Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants. Furlong, C.E., Cole, T.B., Jarvik, G.P., Pettan-Brewer, C., Geiss, G.K., Richter, R.J., Shih, D.M., Tward, A.D., Lusis, A.J., Costa, L.G. Neurotoxicology (2005) [Pubmed]
  10. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Davies, H.G., Richter, R.J., Keifer, M., Broomfield, C.A., Sowalla, J., Furlong, C.E. Nat. Genet. (1996) [Pubmed]
  11. The molecular basis of the human serum paraoxonase activity polymorphism. Humbert, R., Adler, D.A., Disteche, C.M., Hassett, C., Omiecinski, C.J., Furlong, C.E. Nat. Genet. (1993) [Pubmed]
  12. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Cole, T.B., Walter, B.J., Shih, D.M., Tward, A.D., Lusis, A.J., Timchalk, C., Richter, R.J., Costa, L.G., Furlong, C.E. Pharmacogenet. Genomics (2005) [Pubmed]
  13. Evaluation of the paraoxonases as candidate genes for stroke: Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke. Ranade, K., Kirchgessner, T.G., Iakoubova, O.A., Devlin, J.J., DelMonte, T., Vishnupad, P., Hui, L., Tsuchihashi, Z., Sacks, F.M., Sabatine, M.S., Braunwald, E., White, T.J., Shaw, P.M., Dracopoli, N.C. Stroke (2005) [Pubmed]
  14. Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus. Kopprasch, S., Pietzsch, J., Kuhlisch, E., Graessler, J. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  15. Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. Chen, Q., Reis, S.E., Kammerer, C.M., McNamara, D.M., Holubkov, R., Sharaf, B.L., Sopko, G., Pauly, D.F., Merz, C.N., Kamboh, M.I. Am. J. Hum. Genet. (2003) [Pubmed]
  16. Polymorphisms in the PON gene cluster are associated with Alzheimer disease. Erlich, P.M., Lunetta, K.L., Cupples, L.A., Huyck, M., Green, R.C., Baldwin, C.T., Farrer, L.A. Hum. Mol. Genet. (2006) [Pubmed]
  17. Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences. Aviram, M., Rosenblat, M. Curr. Opin. Lipidol. (2005) [Pubmed]
  18. Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles. Marathe, G.K., Zimmerman, G.A., McIntyre, T.M. J. Biol. Chem. (2003) [Pubmed]
  19. PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. Leus, F.R., Zwart, M., Kastelein, J.J., Voorbij, H.A. Atherosclerosis (2001) [Pubmed]
  20. Isolation and complete covalent structure of liver microsomal paraoxonase. Ozols, J. Biochem. J. (1999) [Pubmed]
  21. Increased influence of genetic variation on PON1 activity in neonates. Chen, J., Kumar, M., Chan, W., Berkowitz, G., Wetmur, J.G. Environ. Health Perspect. (2003) [Pubmed]
  22. Apolipoprotein A-I promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by paraoxonase (PON-1) during high density lipoprotein oxidation with a peroxynitrite donor. Ahmed, Z., Ravandi, A., Maguire, G.F., Emili, A., Draganov, D., La Du, B.N., Kuksis, A., Connelly, P.W. J. Biol. Chem. (2001) [Pubmed]
  23. A longitudinal analysis of alteration in lecithin-cholesterol acyltransferase and paraoxonase activities following laparoscopic cholecystectomy relative to other parameters of HDL function and the acute phase response. Kumon, Y., Nakauchi, Y., Kidawara, K., Fukushima, M., Kobayashi, S., Ikeda, Y., Suehiro, T., Hashimoto, K., Sipe, J.D. Scand. J. Immunol. (1998) [Pubmed]
  24. Cysteine substitutions in apolipoprotein A-I primary structure modulate paraoxonase activity. Oda, M.N., Bielicki, J.K., Berger, T., Forte, T.M. Biochemistry (2001) [Pubmed]
  25. Relationships between polymorphisms of the human serum paraoxonase gene and insulin sensitivity in Japanese patients with type 2 diabetes. Ikeda, Y., Suehiro, T., Ohsaki, F., Arii, K., Kumon, Y., Hashimoto, K. Diabetes Res. Clin. Pract. (2003) [Pubmed]
  26. Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy. Kwok, S., Selby, P.L., McElduff, P., Laing, I., Mackness, B., Mackness, M.I., Prais, H., Morgan, J., Yates, A.P., Durrington, P.N., Sci, F.M. Clin. Endocrinol. (Oxf) (2004) [Pubmed]
  27. Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. Mackness, B., Mackness, M.I., Arrol, S., Turkie, W., Julier, K., Abuasha, B., Miller, J.E., Boulton, A.J., Durrington, P.N. Atherosclerosis (1998) [Pubmed]
  28. Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells. Mackness, B., Hine, D., Liu, Y., Mastorikou, M., Mackness, M. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  29. Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization. Aharoni, A., Gaidukov, L., Yagur, S., Toker, L., Silman, I., Tawfik, D.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  30. Association of CYP17, GSTP1, and PON1 polymorphisms with the risk of prostate cancer. Antognelli, C., Mearini, L., Talesa, V.N., Giannantoni, A., Mearini, E. Prostate (2005) [Pubmed]
  31. Distribution spectrum of paraoxonase activity in HDL fractions. Bergmeier, C., Siekmeier, R., Gross, W. Clin. Chem. (2004) [Pubmed]
  32. Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy. Mackness, B., Durrington, P.N., Abuashia, B., Boulton, A.J., Mackness, M.I. Clin. Sci. (2000) [Pubmed]
  33. The active site of human paraoxonase (PON1). Josse, D., Lockridge, O., Xie, W., Bartels, C.F., Schopfer, L.M., Masson, P. Journal of applied toxicology : JAT. (2001) [Pubmed]
  34. The role of paraoxonase 1 activity in cardiovascular disease: potential for therapeutic intervention. Mackness, M.I., Durrington, P.N., Mackness, B. American journal of cardiovascular drugs : drugs, devices, and other interventions. (2004) [Pubmed]
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