Advertisement

Aspirin is a substrate for paraoxonase-like activity: Implications in atherosclerosis

      Abstract

      Paraoxonase 1 (PON 1) is an enzyme that is promiscuous in its ability to hydrolyze various types of substrates. It hydrolyzes aryl esters, phosphate esters, lactones, and reduces lipid peroxides to hydroxides. Aspirin is an aryl ester with a short plasma half life. We hypothesized that aspirin would be effectively hydrolyzed by PON 1 and many of its anti-atherogenic effects, at least in part, could be accounted for by its antioxidant product, salicylic acid. In this study, we determined the ability of human plasma and PON 1-rich HDL to hydrolyze acetyl ester of salicylic acid (aspirin). The ability of aspirin to compete for the hydrolysis of paraoxon and p-nitrophenylacetate was determined. In addition, nitrated aspirin was synthesized and tested directly for hydrolysis. Aspirin competed for the hydrolysis of paraoxon and p-nitrophenylacetate by HDL in a dose-dependent manner. Human plasma and HDL were also able to hydrolyze nitroaspirin and aspirin and release nitrosalicylic acid and salicylic acid, respectively. These findings suggest that salicylic acid might be generated in the plasma from aspirin. The ability of long-term treatment with aspirin to retard atherosclerosis might be dependent on the generation of free salicylic acid, a scavenger of free radicals.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bredie S.J.
        • Wollersheim H.
        • Verheugt F.W.
        • Thien T.
        Low-dose aspirin for primary prevention of cardiovascular disease.
        Semin Vasc Med. 2003; 3: 177-184
        • van Gijn J.
        • Algra A.
        Aspirin and stroke prevention.
        Thromb Res. 2003; 110: 349-353
        • Breddin H.K.
        Aspirin and platelet function.
        J Thromb Haemost. 2004; 2: 1216-1218
        • Cyrus T.
        • Yao Y.
        • Tung L.X.
        • Pratico D.
        Stabilization of advanced atherosclerosis in low-density lipoprotein receptor-deficient mice by aspirin.
        Atherosclerosis. 2006; 184: 8-14
        • Rus H.
        • Niculescu F.I.
        Inflammation, aspirin, and the risk of cardiovascular disease.
        N Engl J Med. 1997; 337 (author reply 423–4): 423
        • Paul A.
        • Calleja L.
        • Camps J.
        • et al.
        The continuous administration of aspirin attenuates atherosclerosis in apolipoprotein E-deficient mice.
        Life Sci. 2000; 68: 457-465
        • Wallace J.L.
        • Ignarro L.J.
        • Fiorucci S.
        Potential cardioprotective actions of no-releasing aspirin.
        Nat Rev Drug Discov. 2002; 1: 375-382
        • Verbeeck R.K.
        • Blackburn J.L.
        • Loewen G.R.
        Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs.
        Clin Pharmacokinet. 1983; 8: 297-331
        • Scheier L.
        Salicylic acid: one more reason to eat your fruits and vegetables.
        J Am Diet Assoc. 2001; 101: 1406-1408
        • La Du B.
        Human serum paraoxonase/arylesterase.
        in: Inc P.P. Pharmacogenetics of Drug Metabolism. Kalow W., New York1992: 51-91
        • La Du B.N.
        Structural and functional diversity of paraoxonases.
        Nat Med. 1996; 2: 1186-1187
        • Navab M.
        • Hama-Levy S.
        • Van Lenten B.J.
        • et al.
        Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio.
        J Clin Invest. 1997; 99: 2005-2019
        • Ng C.J.
        • Shih D.M.
        • Hama S.Y.
        • et al.
        The paraoxonase gene family and atherosclerosis.
        Free Radic Biol Med. 2005; 38: 153-163
        • Abbott C.A.
        • Mackness M.I.
        • Kumar S.
        • Boulton A.J.
        • Durrington P.N.
        Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins.
        Arterioscler Thromb Vasc Biol. 1995; 15: 1812-1818
        • Mackness B.
        • Davies G.K.
        • Turkie W.
        • et al.
        Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype?.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1451-1457
        • Chung B.H.
        • Wilkinson T.
        • Geer J.C.
        • Segrest J.P.
        Preparative and quantitative isolation of plasma lipoproteins: rapid, single discontinuous density gradient ultracentrifugation in a vertical rotor.
        J Lipid Res. 1980; 21: 284-291
        • De Geest B.
        • Stengel D.
        • Landeloos M.
        • et al.
        Effect of overexpression of human apo A-I in C57BL/6 and C57BL/6 apo E-deficient mice on 2 lipoprotein-associated enzymes, platelet-activating factor acetylhydrolase and paraoxonase. Comparison of adenovirus-mediated human apo A-I gene transfer and human apo A-I transgenesis.
        Arterioscler Thromb Vasc Biol. 2000; 20: E68-E75
        • Navab M.
        • Hama S.Y.
        • Anantharamaiah G.M.
        • et al.
        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: 1495-1508
        • Hoak J.C.
        Mechanisms of action: aspirin.
        Thromb Res Suppl. 1983; 4: 47-51
        • Kalgutkar A.S.
        • Crews B.C.
        • Rowlinson S.W.
        • et al.
        Aspirin-like molecules that covalently inactivate cyclooxygenase-2.
        Science. 1998; 280: 1268-1270
        • Xiao G.
        • Tsai A.L.
        • Palmer G.
        • et al.
        Analysis of hydroperoxide-induced tyrosyl radicals and lipoxygenase activity in aspirin-treated human prostaglandin H synthase-2.
        Biochemistry. 1997; 36: 1836-1845
        • Lecomte M.
        • Laneuville O.
        • Ji C.
        • DeWitt D.L.
        • Smith W.L.
        Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin.
        J Biol Chem. 1994; 269: 13207-13215
        • Van Der Ouderaa F.J.
        • Buytenhek M.
        • Nugteren D.H.
        • Van Dorp D.A.
        Acetylation of prostaglandin endoperoxide synthetase with acetylsalicylic acid.
        Eur J Biochem. 1980; 109: 1-8
        • La Du B.
        Plasma esterase activity and the metabolism of drugs with ester groups.
        Ann NY Acad Sci. 1971; 179: 684-694
        • White K.N.
        • Hope D.B.
        Partial purification and characterization of a microsomal carboxylesterase specific for salicylate esters from guinea-pig liver.
        Biochim Biophys Acta. 1984; 785: 138-147
        • Blatter-Garin M.C.
        • Kalix B.
        • De Pree S.
        • James R.W.
        Aspirin use is associated with higher serum concentrations of the anti-oxidant enzyme, paraoxonase-1.
        Diabetologia. 2003; 46: 593-594
        • Cyrus T.
        • Sung S.
        • Zhao L.
        • et al.
        Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice.
        Circulation. 2002; 106: 1282-1287
        • Maree A.O.
        • Fitzgerald D.J.
        Aspirin and coronary artery disease.
        Thromb Haemost. 2004; 92: 1175-1181
        • Frishman W.H.
        Cyclooxygenase inhibition in patients with coronary artery disease.
        J Am Coll Cardiol. 2004; 43: 532-533
        • Adams P.C.
        • Badimon J.J.
        • Badimon L.
        • Chesebro J.H.
        • Fuster V.
        Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty.
        Cardiovasc Clin. 1987; 18: 49-71
        • Amann R.
        • Peskar B.A.
        Anti-inflammatory effects of aspirin and sodium salicylate.
        Eur J Pharmacol. 2002; 447: 1-9
        • Betts W.H.
        • Whitehouse M.W.
        • Cleland L.G.
        • Vernon-Roberts B.
        In vitro antioxidant properties of potential biotransformation products of salicylate, sulphasalazine and amidopyrine.
        J Free Radic Biol Med. 1985; 1: 273-280
        • Drew J.E.
        • Arthur J.R.
        • Farquharson A.J.
        • et al.
        Salicylic acid modulates oxidative stress and glutathione peroxidase activity in the rat colon.
        Biochem Pharmacol. 2005; 70: 888-893
        • Gelvan D.
        • Moreno V.
        • Gassmann W.
        • Hegenauer J.
        • Saltman P.
        Metal-ion-directed site-specificity of hydroxyl radical detection.
        Biochim Biophys Acta. 1992; 1116: 183-191
        • Aviram M.
        • Rosenblat M.
        • Billecke S.
        • et al.
        Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants.
        Free Radic Biol Med. 1999; 26: 892-904
        • Karabina S.A.
        • Lehner A.N.
        • Frank E.
        • Parthasarathy S.
        • Santanam N.
        Oxidative inactivation of paraoxonase-implications in diabetes mellitus and atherosclerosis.
        Biochim Biophys Acta. 2005; 1725: 213-221