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Review Article

The paraoxonases: role in human diseases and methodological difficulties in measurement

, &
Pages 83-106 | Received 20 Aug 2008, Accepted 10 Nov 2008, Published online: 01 Mar 2009

References

  • Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 1996; 33: 498–507.
  • Sorenson RC, Primo-Parmo SL, Camper SA, La Du BN. The genetic mapping and gene structure of mouse paraoxonase/arylesterase. Genomics 1995; 30: 431–438.
  • La Du BN. Human serum paraoxonase/arylesterase. In Kalow W, Ed. Pharmacogenetics of Drug Metabolism. Pp 51–91. New York: Pergamon Press, 1992.
  • Leviev I, Negro F, James RW. Two alleles of the human paraoxonase gene produce different amounts of mRNA. Arterioscler Thromb Vasc Biol 1997; 17: 2935–2939.
  • Sierksma A, van der Gaag MS, van Tol A, James RW, Hendriks FJ. Kinetics of HDL cholesterol and paraoxonase activity in moderate alcohol consumers. Alcohol Clin Exp Res 2002; 26: 1430–1435.
  • Jaouad L, de Guise C, Berrougui H, Cloutier M, Isabelle M, Fulop T, Pavette H, Khalil A. Age-related decreased in high-density lipoproteins antioxidant activity is due to an alteration in the PON1s free sulfhydryl groups. Atherosclerosis 2006; 185: 191–200.
  • Ng CJ, Wadleigh DJ, Gangopadhyay A, Hama S, Grijalva VR, Navab M, Fogelman AM, Reddy ST. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 2001; 276: 44444–44449.
  • Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C, La Du BN. Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab Dispos 2000; 28: 1335–1342.
  • Costa LG, Cole TB, Vitalone A, Furlong CE. Measurement of paraoxonase (PON1) status as a potential biomarker of susceptibility to organophosphate toxicity. Clin Chim Acta 2005; 352: 37–47.
  • Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res 2005; 46: 1239–1247.
  • Aviram M, Rosenblat M. Paraoxonases 1, 2, and 3, oxidative stress, and macrophage cell formation during atherosclerosis development. Free Rad Biol Med 2004; 37: 1304–1316.
  • Horke S, Witte I, Wilgenbus P, Krüger M, Strand D, Förstermann U. Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation. Circulation 2007; 115: 2055–2064.
  • Mackness B, Quarck R, Verreth W, Mackness M, Holvoet P. Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 1545–1550.
  • Ng CJ, Hama SY, Bourquard N, Navab M, Reddy ST. Adenovirus mediated expression of human paraoxonase 2 protects against the development of atherosclerosis in apolipoprotein E-deficient mice. Mol Genet Metab 2006; 89: 368–373.
  • Shih DM, Xia YR, Wang XP, Wang SS, Bourquard N, Fogelman AM, Lusis AJ, Reddy ST. Decreased obesity and atherosclerosis in human paraoxonase 3 transgenic mice. Circ Res 2007; 100: 1200–1207.
  • Ng CJ, Bourquard N, Hama SY, Shih D, Grijalva VR, Navab M, Fogelman AM, Reddy ST. Adenovirus-mediated expression of human paraoxonase 3 protects against the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27: 1368–1374.
  • Aldridge WN. Serum esterases I. Two types of esterase (A and B) hydrolysing p-nitrophenyl acetate, propionate and butyrate and a method for their determination. Biochem J 1953; 53: 110–117.
  • Aldridge WN. Serum esterases II. An enzyme hydrolysing diethyl p-nitrophenyl acetate (E600) and its identity with the A-esterase of mammalian sera. Biochem J 1953; 53: 117–124.
  • Marsillach J, Parra S, Ferré N, Coll B, Alonso-Villaverde C, Joven J, Camps J. Paraoxonase-1 in chronic liver diseases, neurological diseases, and HIV infection. In Mackness B, Mackness M, Aviram M, Paragh G, Eds. The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism. Pp 187–198. Dordrecht: Springer, 2008.
  • Diepgen TL, Geldmacher von Mallinkrodt M. The human serum paraoxonase polymorphism. Arch Toxicol Suppl 1986; 9: 154–158.
  • Furlong CE. Paraoxonases: an historical perspective. In Mackness B, Mackness M, Aviram M, Paragh G, Eds. The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism. Pp 3–31. Dordrecht: Springer, 2008.
  • Davies HG, Richter RJ, Keifer M, Broomfield C, Sowalla J, Furlong CE. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet 1996; 14: 334–336.
  • Eckerson HW, Romson J, Wyte C, La Du BN. The human serum paraoxonase polymprphism: identification of phenotypes by their response to salts. Am J Hum Genet 1983; 35: 214–227.
  • Eckerson HW, Wyte CM, La Du BN. The human serum paraoxonase/arylesterase polymorphism Am J Hum Genet 1983; 35: 1126–1138.
  • Adkins S, Gan Kn, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191 for the respective A or B allozymes. Am J Hum Genet 1993; 52: 598–608.
  • Garin MC, James RW, Dussoix P, Blanché H, Passá P, Froguel P, Ruiz J. Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest 1997; 99: 62–66.
  • Ruiz J, Blanché H, James RW, Garin MC, Vaisse C, Charpentier G, Cohen N, Morabia A, Passa P, Froguel P. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet 1995; 346: 869–872.
  • Serrato M, Marian AJ. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. J Clin Invest 1995; 96: 3005–3008.
  • Mackness B, Mackness MI, Durrington PN, Arrol S, Evans AE, McMaster D, Ferriéres J, Ruidavets JB, Williams NR, Howard AN. Paraoxonase activity in two healthy populations with differing rates of coronary heart disease. Eur J Clin Invest 2000; 30: 4–10.
  • Hassett C, Richter RJ, Humbert R, Chapline C, Crabb JW, Omiecinski CJ, Furlong CE. Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence. Biochemistry 1991; 30: 10141–10149.
  • Marsillach J, Mackness B, Mackness M, Riu F, Beltrán R, Joven J, Camps J. Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Rad Biol Med 2008; 45: 146–157.
  • Pellin MC, Moretto A, Lotti M, Vilanova E. Distribution and some biochemical properties of rat paraoxonase activity. Neurotoxicol Teratol 1990; 12: 611–614.
  • Gil F, Pla A, Gonzalvo MC, Hernández AF, Villanueva E. Rat liver paraoxonase: subcellular distribution and characterization. Chem Biol Interact 1993; 87: 149–154.
  • Gil F, Pla A, Gonzalvo MC, Hernández AF, Villanueva E. Partial purification of paraoxonase from rat liver. Chem Biol Interact 1993; 87: 69–75.
  • Huang YS, Woods L, Sultatos LG. Solubilization and purification of A-esterase from mouse hepatic microsomes. Biochem Pharmacol 1994; 48: 1273–1280.
  • Rodrigo L, Gil F, Hernández AF, Marina A, Vazquez J, Pla A. Purification and characterization of paraoxon hydrolase from rat liver. Biochem J 1997; 321: 595–601.
  • Gonzalvo MC, Gil F, Hernández AF, Villanueva E, Pla A. Inhibition of paraoxonase activity in human liver microsomes by exposure to EDTA, metals and mercurials. Chem Biol Interact 1997; 105: 169–179.
  • Feingold KR, Memon RA, Moser AH, Grunfeld C. Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 1998; 139: 307–315.
  • Esterbauer H, Cheeseman KH. Determination of aldehydic peroxidation products: malondialdehyde and 4-hydroxynonenal. Methods Enzymol 1990; 186: 407–421.
  • Rodrigo L, Hernández AF, López-Caballero JJ, Gil F, Pla A. Immunohistochemical evidence for the expression and induction of paraoxonase in rat liver, kidney, lung and brain tissue. Implications for its physiological role. Chem Biol Interact 2001; 137: 123–137.
  • Mackness MI, Arrol S, Durrington PN. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett 1991; 286: 152–154.
  • Mackness MI, Arrol S, Abbott CA, Durrington PN. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 1993; 104: 129–135.
  • Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, Shih DM, Van Lenten BJ, Frank JS, Demer LL, Edwards DA, Fogelman AM. The yin and yang of oxidation in the development of the fatty streak: a review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol 1996; 16: 152–154.
  • Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN. Paraoxonase inhibits high density lipoprotein (HDL) oxidation and preserves its functions: a possible peroxidative role for paraoxonase. J Clin Invest 1998; 101: 1581–1590.
  • Aviram M, Billecke S, Sorenson R, Bisgaier C, Newton RS, Rosenblat M, Erogul J, Hsu C, Dunlp C, La Du BN. Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different from that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase allozymes Q and R. Arterioscler Thromb Vasc Biol 1998; 18: 1617–1624.
  • Mackness MI, Durrington PN, Mackness B. How high-density lipoprotein protects against the effects of lipid peroxidation. Curr Opin Lipidol 2000; 11: 383–388.
  • Ahmed Z, Ravandi A, Maguire GF, Emili A, Draganov DI, La Du BN, Kuksis A, Connelly PW. 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. J Biol Chem 2001; 276: 24473–24481.
  • Sanvanich P, Mackness B, Gaskell SJ, Durrington P, Mackness M. The effect of high-density lipoproteins on the formation of lipid/protein conjugates during in vitro oxidation of low-density lipoprotein. Biochem Biophys Res Commun 2003; 300: 501–506.
  • Mertens A, Verhamme P, Bielicji JK, Phillips MC, Quarck R, Verreth W, Stengel D, Ninio E, Navab M, Mackness B, Mackness M, Holvoet P. Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation 2003; 107: 1640–1646.
  • Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, Castellani LW, Furlong CE, Costa LG, Fogelman AM, Lusis AJ. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 1998; 394: 284–287.
  • Shih DM, Xia YR, Miller E, Castellani LW, Subbanagounder G, Cheroutre H, Faull KF, Berliner JA, Witztum JL, Lusis AJ. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 2000; 275: 17527–17535.
  • Tward A, Xia YR, Wang XP, Shi YS, Park C, Castellani LW, Lusis AJ, Shih DM. Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 2002; 106: 484–490.
  • Oda MN, Bielicki JK, Ho TT, Berger T, Rubin EM, Forte TM. Paraoxonase 1 overexpression in mice and its effect of high-density lipoproteins. Biochem Biophys Res Commun 2002; 290: 921–927.
  • Mackness B, Durrington PN, Mackness MI. Lack of protection against oxidative modification of LDL by avian HDL. Biochem Biophys Res Commun 1998; 247: 443–446.
  • Teiber JF, Draganov DI, La Du B. Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH. J Lipid Res 2004; 45: 2260–2268.
  • Rosenblat M, Karry R, Aviram M. Paraoxonase 1 (PON1) is a more potent antioxidant and stimulant of macrophage cholesterol efflux, when present in HDL than in lipoprotein-deficient serum: relevance to diabetes. Atherosclerosis 2006; 187: 74.e1–74.e10.
  • Rozenberg O, Shiner M, Aviram M, Hayek T. Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties. Free Rad Biol Med 2008; 44: 1951–1959.
  • Liu Y, Mackness B, Mackness M. Comparison of the ability of paraoxonases 1 and 3 to attenuate the in vitro oxidation of low-density lipoprotein and reduce macrophage oxidative stress. Free Rad Biol Med 2008; 45: 743–748.
  • Aviram M, Rosenblat M, Billecke S, Erogul J, Sorenson R, Bisgaier CL, Newton RS, La Du B. Human serum paraoxonase (PON1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants. Free Rad Biol Med 1999; 26: 892–904.
  • Rozenberg O, Aviram M. S-glutathionylation regulates HDL-associated paraoxonase 1 (PON1) activity. Biochem Biophys Res Commun 2006; 351: 492–498.
  • Jakubowski H. Calcium-dependent human serumhomocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J Biol Chem 2000; 275: 3957–3962.
  • Teiber JF, Draganov DI, La Du BN. Lactonase and lactonizing activities of human serum paraoxonase (PON1) and rabbit serum PON3. Biochem Pharmacol 2003; 66: 887–896.
  • Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J, Furlong CE. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet 1996; 14: 334–336.
  • Teiber JF, Billecke SS, La Du BN, Draganov DI. Estrogen esters as substrates for human paraoxonases. Arch Biochem Biophys 2007; 461: 24–29.
  • La Du BN, Aviram M, Billecke S, Navab M, Primo-Parmo S, Sorenson RC, Standiford TJ. On the physiological role(s) of the paraoxonases. Chem Biol Interact 1999; 119-120: 379–388.
  • Biggadike K, Angell RM, Burgess CM, Farrell RM, Hancock AP, Harker AJ, Irving WR, Ioannou C, Procopiou PA, Shaw RE, Solanke YE, Singh OM, Snowden MA, Stubbs RJ, Walton S, Weston HE. Selective plasma hydrolysis of glucocorticoid gamma-lactones and cyclic carbonates by the enzyme paraoxonase: an ideal plasma inactivation mechanism. J Med Chem 2000; 43: 19–21.
  • Rodrigo L, Mackness B, Durrington PN, Hernández A, Mackness MI. MI Hydrolysis of platelet-activating factor by human serum paraoxonase. Biochem J 2001; 354: 1–7.
  • Marathe G, Zimmerman G, McIntyre T. Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles. J Biol Chem 2003; 278: 3937–3947.
  • Kaur J, Sharma R. Directed evolution: an approach to engineer enzymes. Crit Rev Biotechnol 2006; 26: 165–199.
  • Johannes TW, Zhao H. Directed evolution of enzymes and biosynthetic pathways. Curr Opin Microbiol 2006; 9: 261–267.
  • Bershtein S, Tawfik DS. Advances in laboratory evolution of enzymes. Curr Opin Chem Biol 2008; 12: 151–158.
  • Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R, Dvir H, Ravelli RB, McCarthy A, Toker L, Silman I, Sussman JL, Tawfik DS. Structure and evolution of the human serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol 2004; 11: 412–419.
  • Khersonsky O, Roodveldt C, Tawfik DS. Enzyme promiscuity: evolutionary and mechanistic aspects. Curr Opin Chem Biol 2006; 10: 498–508.
  • Jensen RA. Enzyme recruitment in the evolution of new function. Annu Rev Microbiol 1974; 30: 409–425.
  • O’Brien PJ, Herschlag D. Catalytic promiscuity and the evolution of new enzymatic activities. Chem Biol 1999; 6: R91–R105.
  • Copley SD. Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr Opin Chem Biol 2003; 7: 265–272.
  • Bornscheuer UT, Kazlauskas RJ. Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways. Angew Chem Int Engl 2004; 43: 6032–6040.
  • Kazlauskas RJ. Enhancing catalytic promiscuity for biocatalysis. Curr Opin Chem Biol 2005; 9: 195–201.
  • Aharoni A, Gaidukov L, Yagur S, Toker L, Silman I, Tawfik DS. Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization. Proc Natl Acad Sci USA 2004; 101: 482–487.
  • Aharoni A, Gaidukov L, Khersonsky O, McQGould S, Roodveldt C, Tawkif DS. The ‘evolvability’ of promiscuous protein functions. Nat Genet 2005; 37: 73–76.
  • Khersonsky O, Tawfik DS. Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase. Biochemistry 2005; 44: 6371–6382.
  • Aharoni A, Amitai G, Bernath K, Magdassi S, Tawfik DS. High-throughput screening of enzyme libraries: thiolactonases evolved by fluorescence-activated sorting of single cells in emulsion compartments. Chem Biol 2005; 12: 1281–1289.
  • Khersonsky O, Tawfik DS. The histidine 115-histidine 134 mediates the lactonase activity of mammalian serum paraoxonases. J Biol Chem 2006; 281: 7649–7656.
  • Rosenblat M, Gaidukov L, Khersonsky O, Vaya J, Oren R, Tawfik DS, Aviram M. The catalytic histidine dyad of high density liproprotein-associated serum paraoxonase-1 (PON1) is essential for PON1-mediated inhibition of low density lipoprotein oxidation and stimulation of macrophage cholesterol efflux. J Biol Chem 2006; 182: 7657–7665.
  • Rosenblat M, Vaya J, Shih D, Aviram M. Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: a possible role for lysophosphatidylcholine. Atherosclerosis 2005; 179: 69–77.
  • Tavori H, Khatib S, Aviram M, Vaya J. Characterization of the PON1 active site usind modeling simulation, in relation to PON1 lactonase activity. Bioorg Med Chem 2008; 16: 7504–7509.
  • Navab M, Ananthramaiah GM, Reddy ST, Van Lenten BJ, Ansell BJ, Fonarow GC, Vahabzadeh K, Hama S, Hough G, Kamranpour N, Berliner JA, Lusis AJ, Fogelman AM. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res 2004; 45: 993–1007.
  • Navab M, Hama SY, Cooke CJ, Anantharamaiah GM, Chaddha M, Jin L, Subbanagounder G, Faull KF, Reddy ST, Miller NE, Fogelman AM. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1. J Lipid Res 2000; 41: 1481–1484.
  • Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, Reddy ST, Sevanian A, Fonarow GC, Fogelman AM. Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res 2000; 41: 1485–1508.
  • Negre-Salvayre A, Dousset N, Ferretti G, Bacchetti T, Curatola G, Salvayre R. Antioxidant and cytoprotective properties of high-density lipoproteins in vascular cells. Free Rad Biol Med 2006; 41: 1031–1040.
  • Clay MA, Pyle DH, Rye KA, Vadas MA, Barter PJ. Time sequence of inhibition of endothelial adhesion molecule expression by reconstituted high density lipoproteins. Atherosclerosis 2001; 157: 23–29.
  • Cockerill GW, Rye KA, Gamble JR, Vadas MA, Barter PJ. High density lipoproteins inhibit cytokine induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 1995; 15: 1987–1994.
  • Calabresi L, Gomaraschi M, Vilia B, Omobani L, Dmitrieff C, Franceschini GE. Elevated soluble adhesion molecules in subjects with low HDL-cholesterol. Arterioscler Thromb Vasc Biol 2002; 22: 656–661.
  • Cockerill GW, Huckins TY, Weerasinglme A, Stocker C, Lerch PG, Miller NE, Haskard DO. Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation. Circulation 2001; 103: 108–112.
  • Cockerill GW, McDonald MC, Mota-Filipe H, Cuzzocrea S, Miller NE, Thiemermann C. High density lipoproteins reduce organ injury and organ dysfunction in a rat model of hemorrhagic shock. FASEB J 2001; 15: 1941–1952.
  • Birjmohun RS, Van Leuven SI, Levels JHM, Van’t Veer C, Kuivenhoven JA, meijers JCM, Levi M, Kastelein JJP, Van der Poll T, Stroes ESG. High-density lipoprotein attenuates inflammation and coagulation on endotoxin challenge in humans. Arterioscler Thromb Vasc Biol 2007; 27: 1153–1158.
  • Simpson KJ, Henderson NC, Bone-Larson CL, Lukacs NW, Hogaboam CM, Kunkel SL. Chemokines in the pathogenesis of liver disease: so many players with poorly defined roles. Clin Sci (Lond) 2003; 104: 47–63.
  • Parola M, Bellomo G, Robino G, Barrera G, Dianzani MU. 4-Hydroxynonenal as a biological signal: molecular basis and pathophysiological implications. Antioxidant Redox Signaling 1999; 1: 255–284.
  • Zamara E, Novo E, Marra F, Gentilini A, Romanelli RG, Caligiuri A, Robino G, Tamagno E, Aragno M, Danni O, Autelli R, Colombatto S, Dianzani MU, Pinzani M, Parola M. 4-Hydroxynonenal as a selective pro-fibrogenic stimulus for activated human hepatic stellate cells. J Hepatol 2004; 40: 60–68.
  • Navab M, Berliner JA, Subbanagounder G, Hama S, Lusis AJ, Castellani LW, Reddy S, Shih D, Shi W, Watson AD, Van Lenten BJ, Vora D, Fogelman AM. HDL and the inflammatory response induced by LDL-derived oxidised phospholipids. Arterioscler Thromb Vasc Biol 2001; 21: 481–488.
  • Navab M, Imes SS, Hama SY, Hough GP, Ross LA, Bork RW, Valente AJ, Berliner JA, Drinkwater DC, Laks H, Fogelman AM. Monocyte transmigration induced by modification of low density lipoprotein in cocultures 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 1991; 88: 2039–2046.
  • Watson AD, Berliner JA, Hama SY, La Du BN, Fault KF, Fogelman AM, Navab M. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidised low-density lipoprotein. J Clin Invest 1995; 96: 2882–2891.
  • Mackness B, Hine D, Liu Y, Mastorikou M, Mackness M. Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells. Biochem Biophys Res Commun 2004; 318: 680–683.
  • Tward A, Xia YR, Wang XP, Shi YS, Park C, Castellani LW, Lusis AJ, Shih DM. Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 2002; 106: 484–490.
  • Rozenberg O, Rosenblat M, Coleman R, Shih DM, Aviram M. Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. Free Rad Biol Med 2003; 34: 774–784.
  • Moore RE, Navab M, Millar JS, Zimetti F, Hama S, Rothblat GH, Rader DJ. Increased atherosclerosis in mice lacking apolipoprotein A-I attributable to both impaired cholesterol transport and increased inflammation. Circ Res 2005; 97: 763–771.
  • Ng DS, Chu T, Esposito B, Hui P, Connelly PW, Gross PL. Paraoxonase-1 deficiency in mice predisposes to vascular inflammation, oxidative stress, and thrombogenicity in the absence of hyperlipidemia. Cardiovasc Pathol 2008; 17: 226–232.
  • Verreth W, De KD, Pelat M, Verhamme P, Ganame J, Bielicki JK, Mertens A, Quarck R, Benhabiles N, Marguerie G, Mackness B, Mackness M, Ninio E, Herregods MC, Balligand JL, Holvoet P. Weight loss-associated induction of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma correlate with reduced atherosclerosis and improved cardiovascular function in obese insulin-resistant mice. Circulation 2004; 110: 3259–3269.
  • Mertens A, Verhamme P, Bielicki JK, Phillips MC, Quarck R, Verreth W, Stengel D, Ninio E, Navab M, Mackness B, Mackness M, Holvoet P. Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation 2003; 107: 1640–1646.
  • Mackness B, Quarck R, Verreth W, Mackness M, Holvoet P. Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 1545–1550.
  • Khovidhunkit W, Memon RA, Feingold KR, Grunfeld C. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis 2000; 181(Suppl. 3): S462–S472.
  • Samokyszyn VM, Miller DM, Reif DW, Aust SD. Inhibition of superoxide and ferritin-dependent lipid peroxidation by ceruloplasmin. J Biol Chem 1989; 264: 21–26.
  • Ehrenwald E, Chisholm GM, Fox PL. Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J Clin Invest 1994; 93: 1493–1501.
  • Van Lenten BJ, Hama SY, De Beer FC, Stafforini DM, McIntyre TM, Prescott SM, La Du BN, Fogelman AM, Navab M. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. J Clin Invest 1995; 96: 2758–2767.
  • Van Lenten BJ, Reddy ST, Navab M, Fogelman AM. Understanding changes in high density lipoproteins during the acute phase response. Arterioscler Thromb Vasc Biol 2006; 26: 1687–1688.
  • Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Ansell B, Fogelman AM. Mechanisms of disease: proatherogenic HDL—an evolving field. Nature Clin Pract Endocr Metab 2006; 2: 504–511.
  • Cabana VG, Reardon CA, Feng N, Neath S, Lukens J, Getz GS. Serum paraoxonase: effect of the apolipoprotein composition of HDL and the acute phase response. J Lipid Res 2003; 44: 780–792.
  • Bergmeier C, Siekmeier R, Gross W. Distribution spectrum of paraoxonase activity in HDL fractions. Clin Chem 2004; 50: 2309–2315.
  • Ribas V, Sánchez-Quesada J, Antón R, Camacho M, Julve J, Escolà-Gil JC, Vila L, Ordóñez-Llanos J, Blanco-Vaca F. Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties. A new mechanism linking HDL protein composition and antiatherogenic potential. Circ Res 2004; 95: 789–797.
  • Feingold KR, Memon RA, Mosser AH, Grunfeld C. Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 1998; 139: 307–315.
  • Bin Ali A, Zhang Q, Lim YK, Fang D, Retnam L, Lim SK. Expression of major HDL-associated antioxidant PON-1 is gender dependent and regulated during inflammation. Free Rad Biol Med 2003; 34: 824–829.
  • Han CY, Chiba T, Campbell JS, Fausto N, Chaisson M, Orasanu G, Plutzky J, Chait A. Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes. Arterioscler Thromb Vasc Biol 2006; 26: 1806–1813.
  • Datta G, Chaddha M, Hama S, Navab M, Fogelman AM, Garber DW, Mishra VK, Epand RM, Epand RF, Lund-Katz S, Phillips MC, Segrest JP, Anantharamaiah GM. Effects of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide. J Lipid Res 2001; 42: 1096–1104.
  • Navab M, Anantharamaiah GM, Reddy St, Hama S, Hough G, Grijalva VR, Wagner AC, Frank JS, Datta G, Garber D, Fogelman AM. Oral D-4F causes formation of pre-β high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 2004; 109: 3215–3220.
  • Navab M, Anantharamaiah GM, Reddy ST, Hama S, Hough G, Frank JS, Grijalva VR, Ganesh VK, Mishra VK, Palgunachari MN, Fogelman AM. Oral small peptides render HDL antiinflammatory in mice and monkeys and reduce atherosclerosis in apo E null mice. Circ Res 2005; 97: 524–532.
  • Anantharamaiah GM, Mishra VK, Garber DW, Datta G, Handattu SP, Palgunachari MN, Chaddha M, Navab M, Reddy ST, Segrest JP, Fogelman AM. Structural requirements for antioxidative and anti-inflammatory properties of apolipoprotein A-I mimetic peptides. J Lipid Res 2007; 48: 1915–1923.
  • Van Lenten BJ, Wagner AC, Anantharamaiah GM, Hama S, Reddy ST, Fogelman AM. Lipoprotein inflammatory properties and serum amyloid A levels but not cholesterol levels predict lesion area in cholesterol-fed rabbits. J Lipid Res 2007; 48: 2344–2353.
  • Navab M, Anantharamaiah GM, Reddy ST, Van Lenten BJ, Buga GM, Fogelman AM. Peptide mimetics of apolipoproteins improve HDL functions. J Clin Lipidol 2007; 1: 142–147.
  • Bloedon LT, Dunbar R, Duffy D, Pinell-Salles P, Norris R, DeGroot BJ, Movva R, Navab M, Fogelman AM, Rader DJ. Safety, parmacokinetics, and pharmacodynamics of oral apo A-I mimetic peptide D-4F in high risk cardiovascular patients. J Lipid Res 2008; 49: 1344–1352.
  • Bourquard N, Shih DM, Ng CJ, Villa-García N, Nakamura K, Stoltz DA, Ozer E, Grijalva V, Rozengurt N, Hama SY, Zabner J, Navab M, Fogelman AM, Reddy ST. The role of PON2 and PON3 in atherosclerosis and related traits. In Mackness B, Mackness M, Aviram M, Paragh G, Eds. The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism. Pp 103–128. Dordrecht: Springer, 2008.
  • Boright AP, Connelly PW, Brunt JH, Scherer SW, Tsui LC, Hegele RA. Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites. Atherosclerosis 1998; 139: 131–136.
  • Sanghera DK, Aston CE, Saha N, Kamboh MI. DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary artery disease. Am J Hum Genet 1998; 62: 36–44.
  • Reddy ST, Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopadhyay A, Shih DM, Lusis AJ, Navab M, Fogelman AM. Human paraoxonase-3 is an HDL associated-enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler Thromb Vasc Biol 2001; 21: 542–547.
  • Draganov D, Stetson PL, Watson CE, Billecke S, La Du BN. Rabbit serum paraoxonase 3 (PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J Biol Chem 2000; 275: 33435–33442.
  • Teiber JF, Draganov DI, La Du BN. Lactonase and lactonizing activities of human serum paraoxonase (PON1) and rabbit serum PON3. Biochem Pharmacol 2003; 66: 887–896.
  • Ng CJ, Bourquard N, Frijalva V, Hama S, Shih DM, Navab M, Fogelman AM, Lusis AJ, Young S, Reddy ST. Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins. Anti-atherogenic role for paraoxonase-2. J Biol Chem 2006; 281: 29491–29500.
  • Rosenblat M, Draganov D, Watson CE, Bisgaier CL, La Du BN, Aviram M. Mouse macrophage paraoxonase 2 activity is increased whereas paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol 2003; 23: 468–474.
  • Ng CJ, Shih DM, Hama SY, Villa N, Navab M, Reddy ST. The paraoxonase gene family and atherosclerosis. Free Rad Biol Med 2005; 38: 153–163.
  • Horke S, Witte I, Wilgenbus P, Altenhöfer S, Krüger M, Li H, Förstermann U. Protective effect of paraoxonase-2 against ER stress-induced apoptosis is lost upon disturbance of calcium-homeostasis. Biochem J 2008; 416: 395–405.
  • Li HL, Liu DP, Liang CC. Paraoxonase gene polymorphisms, oxidative stress, and diseases. J Mol Med 2003; 81: 766–779.
  • Alves JD, Ames PR. Atherosclerosis, oxidative stress and auto-antibodies in systemic lupus erythematosus and primary antiphospholipid syndrome. Immunobiology 2003; 207: 23–28.
  • Chait A, Han CY, Oram JF, Heinecke JW. Thematic review series: the immune system and atherogenesis,. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? J Lipid Res 2005; 46: 389–403.
  • James RW. A long and winding road: defining the biological role and clinical importance of paraoxonases. Clin Chem Lab Med 2006; 44: 1052–1059.
  • Can Demirdögen B, Türkanoglu A, Bek S, Sanisoglu Y, Demirkaya S, Vural O, Arinç¸ E, Adali O. Paraoxonase/arylesterase ratio, PON1 192Q/R polymorphism and PON1 status are associated with increased risk of ischemic stroke. Clin Biochem 2008; 41: 1–9.
  • Shin BS, Oh SY, Kim YS, Kim KW. The paraoxonase gene polymorphism in stroke patients and lipid profile. Acta Neurol Scand 2008; 117: 237–243.
  • Franco-Pons N, Marsillach J, Joven J, Camps J, Closa D. Serum paraoxonase undergoes inhibition and proteolysis during experimental acute pancreatitis. J Gastrointest Surg 2008; 12: 891–899.
  • Rothem L, Hartman C, Dahan A, Lachter J, Eliakim R, Shamir R. Paraoxonases are associated with intestinal inflammatory diseases and intracellularly localized to the endoplasmic reticulum. Free Rad Biol Med 2007; 43: 730–739.
  • Boehm D, Krzystek-Korpacka M, Neubauer K, Matusiewicz M, Berdowska I, Zielinski B, Paradowski L, Gamian A. Paraoxonase-1 status in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2008; 2009; 15: 93–99.
  • Dirican M, Akca R, Sarandol E, Dilek K. Serum paraoxonase activity in uremic predialysis and hemodialysis patients. J Nephrol 2004; 17: 813–818.
  • Kalogerakis G, Baker AM, Christov S, Rowley KG, Dwyer K, Winterbourn C, Best JD, Jenkins AJ. Oxidative stress and high-density lipoprotein function in Type I diabetes and end-stage renal disease. Clin Sci (Lond) 2005; 108: 497–506.
  • Marsillach J, Martínez-Vea A, Marcas L, Mackness B, Mackness M, Ferré N, Joven J, Camps J. Administration of exogenous erythropoietin beta affects lipid peroxidation and serum paraoxonase-1 activity and concentration in predialysis patients with chronic renal disease and anemia. Clin Exp Pharmacol Physiol 2007; 34: 347–349.
  • Landers JE, Shi L, Cho TJ, Glass JD, Shaw CE, Nigel Leigh P, Diekstra F, Polak M, Rodriguez-Leyva I, Niemann S, Traynor BJ, McKenna-Yasek D, Sapp PC, Al Chalabi A, Wills AM, Brown RH Jr. A common haplotype within the PON1 promoter region is associated with sporadic ALS. Amyotroph Lateral Scler 2008; 10: 1–9.
  • Valdmanis PN, Kabashi E, Dyck A, Hince P, Lee J, Dion P, D’Amour M, Souchon F, Bouchard JP, Salachas F, Meininger V, Andersen PM, Camu W, Dupré N, Rouleau GA. Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden. Neurology 2008; 71: 514–520.
  • Tripi LM, Manzi S, Chen Q, Kenney M, Shaw P, Kao A, Bontempo F, Kammerer C, Kamboh MI. Relationship of serum paraoxonase 1 activity and paraoxonase 1 genotype to risk of systemic lupus erythematosus. Arthritis Rheum 2006; 54: 1928–1939.
  • Kiss E, Seres I, Tarr T, Kocsis Z, Szegedi G, Paragh G. Reduced paraoxonase 1 activity is a risk for atherosclerosis in patients with systemic lupus erythematosus. Ann NY Acad Sci 2007; 1108: 83–91.
  • Stevens VL, Rodriguez C, Pavluck AL, Thun MJ, Calle EE. Association of polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPS-II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2006; 15: 1226–1228.
  • Stevens VL, Rodriguez C, Talbot JT, Pavluck AL, Thun MJ, Calle EE. Paraoxonase 1 (PON1) polymorphisms and prostate cancer in the CPS-II Nutrition Cohort. Prostate 2008; 68: 1336–1340.
  • Elkiran ET, Mar N, Aygen B, Gursu F, Karaoglu A, Koca S. Serum paraoxonase and arylesterase activities in patients with lung cancer in a Turkish population. BMC Cancer 2007; 7: 48.
  • Padungtod C, Niu T, Wang Z, Savitz DA, Christiani DC, Ryan LM, Xu X. Paraoxonase polymorphism and its effect on male reproductive outcomes among Chinese pesticide factory workers. Am J Ind Med 1999; 36: 379–387.
  • Pérez-Herrera N, Polanco-Minaya H, Salazar-Arredondo E, Solís-Heredia MJ, Hernández-Ochoa I, Rojas-García E, Alvarado-Mejía J, Borja-Aburto VH, Quintanilla-Vega B. PON1Q192R genetic polymorphism modifies organophosphorous pesticide effects on semen quality and DNA integrity in agricultural workers from southern Mexico. Toxicol Appl Pharmacol 2008; 230: 261–268.
  • Ozer EA, Pezzulo A, Shih DM, Chun C, Furlong C, Lusis AJ, Greenberg EP, Zabner J. Human and murine paraoxonase 1 are host modulators of Pseudomonas aeruginosa quorum-sensing. FEMS Microbiol Lett 2005; 253: 29–37.
  • Stoltz DA, Ozer EA, Taft PJ, Barry M, Liu L, Kiss PJ, Moninger TO, Parsek MR, Zabner J. Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1. J Clin Invest 2008; 118: 3123–3131.
  • Aslan M, Nazligul Y, Horoz M, Bolukbas C, Bolukbas FF, Gur M, Celik H, Erel O. Serum paraoxonase-1 activity in Helicobacter pylori infected subjects. Atherosclerosis 2008; 196: 270–274.
  • Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs Jr. DR, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989; 79: 8–15.
  • McElveen J, Mackness MI, Colley CM, Peard T, Warner S, Walker CH. Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction. Clin Chem 1986; 32: 671–673.
  • Navab M, Hama-Levy S, Van Lenten BJ, Fonarow GC, Cardinez CJ, Castellani LW, Brennan ML, Lusis AJ, Fogelman AM, La Du BN. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest 1997; 99: 2005–2019.
  • Ayub A, Mackness MI, Arrol S, Mackness B, Patel J, Durrington PN. Serum paraoxonase after myocardial infarction. Arterioscler Thromb Vasc Biol 1999; 19: 330–335.
  • Jarvik GP, Rozek LS, Brophy VH, Hatsukami TS, Richter RJ, Schellenberg GD, Furlong CE. Paraoxonase (PON1) phenotype is a better predictor of vascular disease than its PON1(192) or PON1(55) genotype. Arterioscler Thromb Vasc Biol 2000; 20: 2441–2447.
  • Mackness B, Davies GK, Turkie W, Lee E, Roberts DH, Hill E, Roberts C, Durrington PN, Mackness MI. Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol 2001; 21: 1221–1232.
  • Ferré N, Tous M, Paul A, Zamora A, Vendrell JJ, Bardají A, Camps J, Richart C, Joven J. Paraoxonase Gln-Arg(192) and Leu-Met(55) gene polymorphisms and enzyme activity in a population with a low rate of coronary heart disease. Clin Biochem 2002; 35: 197–203.
  • Mackness B, Durrington P, McElduff P, Yarnell J, Azam N, Watt M, Mackness M. Low paraoxonase activity predicts coronary event in the Caerphilly Prospective Study. Circulation 2003; 22: 2775–2779.
  • Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, Fu X, Shao M, Brennan DM, Ellis SG, Brennan ML, Allayee H, Lusis AJ, Hazen SL. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 2008; 300: 168–169.
  • Aviram M. Introduction to the serial review on paraoxonases, oxidative stress, and cardiovascular diseases. Free Rad Biol Med 2004; 37: 1301–1303.
  • Van Timbergen TM, Van Tits LJH, Roest M, Stalenhoef AFH. The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine. Nether J Med 2006; 64: 34–38.
  • Roest M, Voorbij HAM. PON1 genotypes and coronary heart disease. In Mackness B, Mackness M, Aviram M, Paragh G, Eds. The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism. Pp 139–147. Dordrecht: Springer, 2008.
  • Mackness B, Durrington PN, Mackness MI. Polymorphisms of paraoxonase genes and low-density lipoprotein lipid peroxidation. Lancet 1999; 353: 468–469.
  • Leviev I, Negro F, James RW. Two alleles of the human paraoxonase gene produce different amounts of mRNA. An explanation for differences in serum concentrations of paraoxonase associated with the (Leu-Met54) polymorphism. Arterioscler Thromb Vasc Biol 1997; 17: 2935–2939.
  • Leviev I, James RW. Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations. Arterioscler Thromb Vasc Biol 2000; 20: 516–521.
  • Brophy VH, Hastings MD, Clendenning JB, Richter RJ, Jarvik GP, Furlong CE. Polymorphisms in the human paraoxonase (PON1) promoter. Pharmacogenetics 2001; 11: 77–84.
  • Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh J. Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Lancet 2004; 363: 689–695.
  • Durrington PN, Mackness B, Mackness MI. Paraoxonase polymorphisms and coronary heart disease. Lancet 2004; 364: 579–580.
  • Stamler J, Vaccaro O, Neaton JD, Wentworth D. for the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16: 434–444.
  • James RW, Leviev I, Ruiz J, Passa P, Froguel P, Blatter garin MC. Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. Diabetes 2000; 49: 1390–1393.
  • Leviev I, Kalix B, Brulhart Meynet MC, James RW. The paraoxonase PON1 promoter polymorphism C(-107)T is associated with increased serum glucose concentrations in non-diabetic patients. Diabetologia 2001; 44: 1177–1183.
  • Mastorikou M, Mackness M, Mackness B. Defective metabolism of oxidized phospholipid by HDL from people with type 2 diabetes. Diabetes 2006; 55: 3099–3103.
  • Matsunaga T, Iguchi K, Nakajima T, Koyama I, Miyazaki T, Inoue I, Kawai S, Katayama S, Hirano K, Hokari S, Komoda T. Glycated high-density lipoprotein induces apoptosis of endothelial cells via a mitochondrial dysfunction. Biochem Biophys Res Commun 2001; 287: 714–720.
  • Rozenberg O, Shiner M, Aviram M, Hayek T. Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties. Free Rad Biol Med 2008; 44: 1951–1959.
  • Lee HG, Castellani RJ, Zhu X, Perry G, Smith MA. Amyloid-beta in Alzheimer’s disease: the horse or the cart? Pathogenic or protective? Int J Exp Pathol 2005; 86: 133–138.
  • Mohs RC. The clinical syndrome of Alzheimer’s disease: aspects particularly relevant to clinical trials. Genes Brain Behav 2005; 15: 129–133.
  • Tahl DR, Ghebremedhin E, Orantes M, Wiestler OD. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 2003; 62: 1287–1301.
  • Roher AE, Esh C, Rahman A, Kokjohn TA, Beach TG. Atherosclerosis of cerebral arteries in Alzheimer disease. Stroke 2004; 35: 2623–2627.
  • Kalback W, Esh C, Castano EM, Rahman E, Kokjohn T, Luehrs DC, Sue L, Cisneros R, Gerber F, Richardson C. Atherosclerosis, vascular amyloidosis and brain hypoperfusion in the pathogenesis of sporadic Alzheimer’s disease. Neurol Res 2004; 26: 525–539.
  • Farrer LA. Genetics and the dementia patient. Neurologist 1997; 3: 13–30.
  • Scacchi R, Gambina G, Martini MC, Broggio E, Vilardo T, Corbo RM. Different pattern of association of paraoxonase Gln192-Arg polymorphism with sporadic late-onset Alzheimer’s disease and coronary artery disease. Neurosci Lett 2003; 339: 17–20.
  • He XM, Zhang ZX, Zhang JW, Zhou YT, Tang MN, Wu CB, Hong Z. Gln192Arg polymorphism in paraoxonase 1 gene is associated with Alzheimer disease in a Chinese Han ethnic population. Chin Med J 2006; 119: 1204–1209.
  • Pola R, Gaetani E, Flex A, Gerardino L, Aloi F, Flore R, Serricchio M, Pola P, Bernabei R. Lack of association between Alzheimer’s disease and Gln-Arg 192 Q/R polymorphism of the PON1 gene in an Italian population. Dement Geriatr Cogn Disord 2003; 15: 88–91.
  • Zuliani G, Zanca R, Munari MR, Zurlo A, Vavalle C, Atti AR, Fellin R. Genetic polymorphisms in older subjects with vascular or Alzheimer’s dementia. Acta Neurol Scand 2001; 103: 304–308.
  • Shi J, Zhang S, Tang M, Liu X, Li T, Han H, Wang Y, Guo Y, Zhao J, Li H, Ma C. Possible association between Cys311Ser polymorphism of paraoxonase 2 gene and late-onset Alzheimer’s disease in Chinese. Brain Res Mol Brain Res 2004; 120: 201–204.
  • Erlich PM, Lunetta KL, Cupples LA, Huyck M, Green RC, Baldwin CT, Farrer LA. Polymorphisms in the PON gene cluster are associated with Alzheimer disease. Hum Mol Genet 2006; 15: 77–85.
  • Paragh G, Balla P, Katona E, Seres I, Egerhazi A, Degrell I. Serum paraoxonase activity changes in patients with Alzheimer’s disease and vascular dementia. Eur Arch Psychiatry Clin Neurosci 2002; 252: 63–67.
  • Stanbridge JB. Pharmacotherapeutic approaches to the treatment of Alzheimer’s disease. Clin Ther 2004; 26: 615–630.
  • Costa LG, Vitalone A, Cole TB, Furlong CE. Modulation of paraoxonase (PON1) activity. Biochem Pharmacol 2005; 69: 541–550.
  • Pola R, Flex A, Ciaburri M, Rovella E, Valiani A, Reali G, Silveri MC, Bernabei R. Responsiveness to cholinesterase inhibitors in Alzheimer’s disease: A possible role for the 192 Q/R polymorphism of the PON-1 gene. Neurosci Lett 2005; 382: 338–341.
  • Benmoyal-Segal L, Vander T, Shifman S, Bryk B, Ebstein R, Marcus EL, Stessman J, Darvasi A, Herishanu Y, Friedman A, Soreq H. Acetylcholinesterase/paraoxonase interactions increase the risk of insecticide-induced Parkinson’s disease FASEB J 2005; 19: 452–454.
  • Akhmedova SN, Yakimovsky AK, Schwartz EI. Paraoxonase 1 Met-Leu 54 polymorphism is associated with Parkinson’s disease. J Neurol Sci 2001; 184: 179–182.
  • Carmine A, Buervenich S, Sydow O, Anvret M, Olson L. Further evidence for association of the paraoxonase 1 (PON1) Met-54 allele with Parkinson’s disease. Mov Disord 2002; 17: 764–766.
  • Kelada SN, Costa-Mallen P, Checkoway H, Viernes HA, Farin FM, Smith-Weller T, Franklin GM, Costa LG. Paraoxonase 1 promoter and coding region polymorphisms in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2003; 74: 545–548.
  • Wang J, Liu Z. No association between paraoxonase 1 (PON1) gene polymorphism and susceptibility to Parkinson’s disease in a Chinese population. Mov Disord 2000; 15: 1265–1267.
  • Clarimon J, Eerola J, Hellström O, Tienari PJ, Singleton A. Paraoxonase 1 (PON1) gene polymorphisms and Parkinson’s disease in a Finnish population. Neurosci Lett 2004; 367: 168–170.
  • Zintzaras E, Hadjigeorgiou GM. Association of paraoxonase 1 gene polymorphisms with risk of Parkinson’s disease: a meta-analysis. J Hum Genet 2004; 49: 474–481.
  • Saeed M, Siddique N, Hung WY, Usacheva E, Liu E, Sufit RL, Heller SL, Haines JL, Pericak-Vance M, Siddique T. Paraoxonase cluster polymorphisms are associated with sporadic ALS. Neurology 2006; 67: 771–776.
  • Slowik A, Tomik B, Wolkow PP, Partyka D, Turaj W, Malecki MT, Pera J, Dziedzic T, Szczudlik A, Figlewicz DA. Paraoxonase gene polymorphisms and sporadic ALS. Neurology 2006; 67: 766–770.
  • Ferretti G, Bacchetti T, Principi F, Di Ludovico F, Viti B, Angeleri VA, Danni M, Provinciali L. Increased levels of lipid hydroperoxides in plasma of patients with multiple sclerosis: a relationship with paraoxonase activity. Mult Scler 2005; 11: 677–682.
  • Janel N, Christophe O, Yayha-Graison EA, Hamelet J, Paly E, Prieur M, Delezoïde AL, Delabar JM. Paraoxonase-1expression is up-regulated in Down Syndrome fetal liver. Biochem Biophys Res Commun 2006; 346: 1303–1306.
  • Alonso-Villaverde C, Coll B, Gómez F, Parra S, Camps J, Joven J, Masana L. The efavirenz-induced increase in HDL-cholesterol is influenced by the multidrug resistance gene 1 C3435T polymorphism. AIDS 2005; 19: 341–342.
  • Coll B, Alonso-Villaverde C, Parra S, Montero M, Tous M, Joven J, Masana L. The stromal derived factor-1 mutated allele (SDF1-3’A) is associated with a lower incidence of atherosclerosis in HIV-infected patients. AIDS 2005; 19: 1877–1883.
  • Coll B, Parra S, Alonso-Villaverde C, de Groot E, Aragonés G, Montero M, Tous M, Camps J, Joven J, Masana L. HIV-infected patients with lypodystrophy have higher rates of carotid atherosclerosis: the role of monocyte chemoattractant protein-1. Cytokine 2006; 34: 51–55.
  • Rose H, Woolley I, Hoy J, Dart A, Bryant B, Mijch A, Sviridov D. HIV infection and high-density lipoprotein: the effect of disease vs. the effect of treatment. Metabolism 2006; 55: 90–95.
  • Alonso-Villaverde C, Segués T, Coll-Crespo B, Pérez-Bernalte R, Rabassa A, Gomila M, Parra S, González-Esteban MA, Jiménez-Expósito JM, Masana L. High-density lipoprotein concentrations relate to the clinical course of HIV viral load in patients undergoing antiretroviral therapy. AIDS 2003; 17: 1173–1177.
  • Parra S, Alonso-Villaverde C, Coll B, Ferré N, Marsillach J, Aragonès G, Mackness M, Mackness B, Masana L, Joven J, Camps J. Serum paraoxonase-1 activity and concentration are influenced by human immunodeficiency virus infection. Atherosclerosis 2007; 194: 175–181.
  • Owens BJ, Anantharamaiah GM, Kahlin JB, Srinivas RV, Compans RW, Segrest JP. Apolipoprotein A-I and its amphipathic helix peptide analogues inhibit human immunodeficiency virus-induced syncytium formation. J Clin Invest 1990; 86: 1142–1150.
  • Liao Z, Graham DR, Hildreth JE. Lipid rafts and HIV pathogenesis: virion-associated cholesterol is required for fusion and infection of susceptible cells. AIDS Res Hum Retroviruses 2003; 19: 675–687.
  • Nguyen DH, Hildreth JE. Evidence for budding of human immunodeficiency virus type I selectively from glycolipid-enriched membrane lipid rafts. J Virol 2000; 74: 3264–3272.
  • Ansell BJ, Watson KE, Fogelman AM, Navab M, Fonarow GC. High-density lipoprotein function: recent advances. J Am Coll Cardiol 2005; 46: 1792–1798.
  • Ferré N, Camps J, Cabré M, Paul A, Joven J. Hepatic paraoxonase activity alterations and free radical production in rats with experimental cirrhosis. Metabolism 2001; 50: 997–1000.
  • Burlina A, Galzigna L. Serum arylesterase isoenzymes in chronic hepatitis. Clin Biochem 1974; 7: 202–205.
  • Burlina A, Michielin E, Galzigna L. Characteristics and behaviour of arylesterase in human serum and liver. Eur J Clin Invest 1977; 7: 17–20.
  • Kawai H, Sakamoto F, Inoue Y. Improved specific assay for serum arylesterase using a water-soluble substrate. Clin Chim Acta 1990; 188: 177–182.
  • Ferré N, Camps J, Prats E, Vilella E, Paul A, Figuera L, Joven J. Serum paraoxonase activity: a new additional test for the improved evaluation of chronic liver damage. Clin Chem 2002; 48: 261–268.
  • Ferré N, Marsillach J, Camps J, Rull A, Coll B, Tous M, Joven J. Genetic association of paraoxonase-1 polymorphisms and chronic hepatitis C virus infection.Clin Chim Acta 2005; 361: 206–210.
  • Kilic SS, Aydin S, Kilic N, Erman F, Aydin S, Celik I. Serum arylesterase and paraoxonase activity in patients with chronic hepatitis. World J Gastroenterol 2005; 11: 7351–7354.
  • Aviram M, Hardak E, Vaya J, Mahmood S, Milo S, Hoffman A, Billicke S, Draganov D, Rosenblat M. Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions. PON1 esterase and peroxidase-like activities. Circulation 2000; 101: 2510–2517.
  • Sebastiani G, Alberti A. Non invasive fibrosis biomarkers reduce but not substitute the need for liver biopsy. World J Gastroenterol 2006; 12: 3682–3694.
  • Marsillach J, Ferré N, Vila MC, Lligoña A, Mackness B, Mackness M, Deulofeu R, Solá R, Parés A, Pedro-Botet J, Joven J, Camps J. Serum paraoxonase-1 in chronic alcoholics: relationship with liver disease. Clin Biochem 2007; 40: 645–650.
  • Camps J, Marsillach J, Joven J. Measurement of serum paraoxonase-1 activity as a potential biomarker for chronic liver impairment. Clin Chim Acta 2007; 386: 114–115.
  • Xu GY, Lv GC, Chen Y, Hua YC, Zhu SM, Yang YD. Monitoring the level of serum paraoxonase 1 activity in liver transplantation patients. Hepatobiliary Pancreat Dis Int 2005; 4: 178–181.
  • Sugano M, Tsuchida K, Makino N. High-density lipoproteins protect endothelial cells from tumor necrosis factor-a-induced apoptosis. Biochem Biophys Res Commun 2000; 272: 872–876.
  • Nofer JR, Kehrel B, Fobker M, Levkau B, Assman G, Von Eckardstein A. HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis 2002; 161: 1–16.
  • Ferré N, Marsillach J, Camps J, Mackness B, Mackness M, Riu F, Coll B, Tous M, Joven J. Paraoxonase-1 is associated with oxidative stress, fibrosis and FAS expression in chronic liver diseases. J Hepatol 2006; 45: 51–59.
  • Rao MN, Marmillot P, Gong M, Palmer DA, Seeff LB, Strader DB, Lakshman MR. Light, but not heavy alcohol drinking, stimulates paraoxonase by upregulating liver mRNA in rats and humans. Metabolism 2003; 52: 1287–1294.
  • Erdös EG, Boggs LE. Hydrolysis of paraoxon in mammalian blood. Nature 1961; 190: 716.
  • Mackness MI. Why plasma should not be used to study paraoxonase. Atherosclerosis 1998; 136: 195–196.
  • Mackness MI. Human paraoxonase is inhibited in EDTA plasma. Biochem Biophys Res Commun 1998; 242: 249.
  • Aldridge WN. ‘A’-esterases and ‘B’-esterases in perspective. In Reiner E, Aldridge WN, Hoskin FCG, Eds. Enzymes Hydrolysing Organophosphorous Compounds. Pp 1–14. Chichester: Ellis Horwood, 1989.
  • Jarvik GP, Tsai NT, McKinstry LA, Wani R, Brophy VH, Richter RJ, Schellenberg GD, Heagerty PJ, Hatsukami TS, Furlong CE. Vitamin C and E intake is associated with increased paraoxonase activity. Arterioscler Thromb Vasc Biol 2002; 22: 1329–1333.
  • Martín-Campos JM, Julve J, Escolà JC, Ordóñez-Llanos J, Gómez J, Binimelis J, Gonzàlez-Sastre F, Blanco-Vaca F. Apo A-IMALLORCA impairs LCAT activation and induces dominant familial hypoalphalipoproteinemia. J Lipid Res 2002; 43: 115–123.
  • Ferré N, Camps J, Marsillach J, Mackness B, Mackness M, Coll B, Tous M, Joven J. Comparison of paraoxonase 1 measurements in serum and in lithium-heparin-anticoagulated plasma samples. Clin Chem 2005; 51: 922–923.
  • Guthold M, Liu W, Stephens B, Lord ST, Hantgan RR, Erie DA, Taylor RM Jr, Superf R. Visualization and mechanical manipulations of individual fibrin fibers suggest that fiber cross section has a fractal dimension 1.3. Biophys J 2004; 87: 4226–4236.
  • Mackness Mi, Mackness B, Arrol S, Wood G, Bhatnagar D, Durrington PN. Presence of paraoxonase in human interstitial fluid. FEBS Lett 1997; 416: 377–380.
  • Richter RJ, Jampsa RL, Jarvik GP, Costa LG, Furlong CE. Determination of paraoxonase 1 status and genotypes at specific polymorphic sites. In Maines M, Costa LG, Reed DJ, Hodgson E, Eds. Current Protocols in Toxicology, Pp 4.12.1–1.12.19. New York: John Wiley and Sons, 2004.
  • Haagen L, Brock A. A new automated method for phenotyping arylesterase (EC 3.1.12) based upon inhibition of enzymatic hydrolysis of 4-nitrophenyl acetate by phenyl acetate. Eur J Clin Chem Clin Biochem 1992; 30: 391–395.
  • Furlong CE, Richter RJ, Seidel SL, Costa LG, Motulsky AG. Spectrophotometric assays for the enzymatic hydrolysis of the active metabolites of chlorpyrifos and parathion by plasma paraoxonase/arylesterase. Anal Biochem 1989; 180: 242–247.
  • Davies HG, Richter RJ, Keifer M, Broomfield CA, Sowalla J, Furlong CR. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nature Genet 1996; 14: 334–336.
  • Li WF, Costa LG, Richter RJ, Hagen T, Shih DM, Tward A, Lusis AJ, Furlong CE. Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorous compounds. Pharmacogenetics 2000; 10: 767–779.
  • Cole TB, Walter BJ, Shih DM, Tward AD, Lusis AJ, Timchalk C, Richter RJ, Costa LG, Furlong CE. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenet Genom 2005; 15: 589–598.
  • Jakubowski H. Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. J Biol Chem 2000; 275: 3957–3962.
  • Khersonsky O, Tawfik DS. Chromogenic and fluorogenic assays for the lactonase activity of serum paraoxonases. ChemBioChem 2006; 7: 49–53.
  • Gaidukov L, Tawfik DS. The development of human sera tests for HDL-bound serum PON1 and its lipolactonase activity. J Lipid Res 2007; 48: 1637–1646.
  • Gaidukov L, Rosenblat M, Aviram M, Tawfik DS. The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux. J Lipid Res 2006; 47: 2492–2502.
  • Kawai H, Yomoda S, Inoue I. ELISA using monoclonal antibody to human serum arylesterase. Clin Chim Acta 1991; 202: 219–226.
  • Blatter MC, James RW, Messmer S, Barja F, Pometta D. Identification of a distinct human high-density lipoprotein subspecies defined by a lipoprotein-associated protein, K-45. Identity of K-45 with paraoxonase. Eur J Biochem 1993; 211: 871–879.
  • Blatter-Garin MC, Abbott C, Messmer S, Mackness M, Durrington P, Pometta D, James RW. Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations. Biochem J 1994; 304: 549–554.
  • Mackness B, Hunt R, Durrington PN, Mackness MI. Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis. Arterioscler Thromb Vasc Biol 1997; 17: 1233–1238.
  • James RW, Blatter-Garin MC, Calabresi L, Miccoli R, Von Eckardstein A, Tilly-Kiesi M, Taskinen MR, Assmann G, Franceschini G. Modulated serum activities and concentrations of paraoxonase in high density lipoprotein deficiency states. Atherosclerosis 1998; 139: 77–82.
  • Deakin SP, James RW. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci (Lond) 2004; 107: 425–447.
  • Shamir R, Hartman C, Karry R, Pavlotzky E, Eliakim R, Lachter J, Suissa A, Aviram M. Paraoxonases (PONs) 1, 2, and 3 are expressed in human and mouse gastrointestinal tract and in Caco-2 cell line: Selective secretion of PON1 and PON2. Free Rad Biol Med 2005; 39: 336–344.
  • Suchocka Z, Swatowska J, Pachecka J, Suchocki P. RP-HPLC determination of paraoxonase 3 activity in human blood serum. J Pharm Biomed Anal 2006; 42: 113–119.

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