+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Paraoxonase: Its antiatherogenic role in chronic renal failure

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Paraoxonase (PON) is an aryldialkylphosphatase, which reversibly binds and hydrolyzes organophosphates. The PON family has three members (PON1, PON2 and PON3); they share structural properties and enzymatic activities. PON1 is shown to reside over high density lipoprotein (HDL) and has both antioxidant and antiatherogenic functions. Function of PON2 and PON3 are speculative and still under research. Several methodologies were developed over the years to determine the activity and mass of PON1, of which spectrophotometer-based methods using certain chemicals as substrate predominate. Several studies have shown decreased levels of PON1 in chronic renal failure (CRF) patients, particularly those on hemodialysis. The role of PON1 in development of cardiovascular disease has drawn considerable attention in recent years. Several authors have shown decreased levels of HDL and PON1 activity in CRF patients on hemodialysis and reported this to be a risk factor in the development of CVD. Enhancement or maintenance of the PON1 activity may prevent development of CVDs and its consequences in patients on hemodialysis.

          Related collections

          Most cited references 74

          • Record: found
          • Abstract: found
          • Article: not found

          Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase.

          HDL levels are inversely related to the risk of developing atherosclerosis. In serum, paraoxonase (PON) is associated with HDL, and was shown to inhibit LDL oxidation. Whether PON also protects HDL from oxidation is unknown, and was determined in the present study. In humans, we found serum HDL PON activity and HDL susceptibility to oxidation to be inversely correlated (r2 = 0.77, n = 15). Supplementing human HDL with purified PON inhibited copper-induced HDL oxidation in a concentration-dependent manner. Adding PON to HDL prolonged the oxidation lag phase and reduced HDL peroxide and aldehyde formation by up to 95%. This inhibitory effect was most pronounced when PON was added before oxidation initiation. When purified PON was added to whole serum, essentially all of it became HDL-associated. The PON-enriched HDL was more resistant to copper ion-induced oxidation than was control HDL. Compared with control HDL, HDL from PON-treated serum showed a 66% prolongation in the lag phase of its oxidation, and up to a 40% reduction in peroxide and aldehyde content. In contrast, in the presence of various PON inhibitors, HDL oxidation induced by either copper ions or by a free radical generating system was markedly enhanced. As PON inhibited HDL oxidation, two major functions of HDL were assessed: macrophage cholesterol efflux, and LDL protection from oxidation. Compared with oxidized untreated HDL, oxidized PON-treated HDL caused a 45% increase in cellular cholesterol efflux from J-774 A.1 macrophages. Both HDL-associated PON and purified PON were potent inhibitors of LDL oxidation. Searching for a possible mechanism for PON-induced inhibition of HDL oxidation revealed PON (2 paraoxonase U/ml)-mediated hydrolysis of lipid peroxides (by 19%) and of cholesteryl linoleate hydroperoxides (by 90%) in oxidized HDL. HDL-associated PON, as well as purified PON, were also able to substantially hydrolyze (up to 25%) hydrogen peroxide (H2O2), a major reactive oxygen species produced under oxidative stress during atherogenesis. Finally, we analyzed serum PON activity in the atherosclerotic apolipoprotein E-deficient mice during aging and development of atherosclerotic lesions. With age, serum lipid peroxidation and lesion size increased, whereas serum PON activity decreased. We thus conclude that HDL-associated PON possesses peroxidase-like activity that can contribute to the protective effect of PON against lipoprotein oxidation. The presence of PON in HDL may thus be a major contributor to the antiatherogenicity of this lipoprotein.
            • Record: found
            • Abstract: found
            • Article: not found

            Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities.

            The paraoxonase (PON) gene family in humans has three members, PON1, PON2, and PON3. Their physiological role(s) and natural substrates are uncertain. We developed a baculovirus-mediated expression system, suitable for all three human PONs, and optimized procedures for their purification. The recombinant PONs are glycosylated with high-mannose-type sugars, which are important for protein stability but are not essential for their enzymatic activities. Enzymatic characterization of the purified PONs has revealed them to be lactonases/lactonizing enzymes, with some overlapping substrates (e.g., aromatic lactones), but also to have distinctive substrate specificities. All three PONs metabolized very efficiently 5-hydroxy-eicosatetraenoic acid 1,5-lactone and 4-hydroxy-docosahexaenoic acid, which are products of both enzymatic and nonenzymatic oxidation of arachidonic acid and docosahexaenoic acid, respectively, and may represent the PONs' endogenous substrates. Organophosphates are hydrolyzed almost exclusively by PON1, whereas bulky drug substrates such as lovastatin and spironolactone are hydrolyzed only by PON3. Of special interest is the ability of the human PONs, especially PON2, to hydrolyze and thereby inactivate N-acyl-homoserine lactones, which are quorum-sensing signals of pathogenic bacteria. None of the recombinant PONs protected low density lipoprotein against copper-induced oxidation in vitro.
              • Record: found
              • Abstract: found
              • Article: not found

              Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase.

              We have investigated the Cu2+ induced generation of lipid peroxides in low density lipoprotein (LDL) incubated with high density lipoprotein (HDL) and with purified paraoxonase, an enzyme normally resident on HDL. HDL (1.5 mg) and paraoxonase (20 micrograms) inhibited lipid peroxide generation in LDL by 32% and 25%, respectively after 24 h of incubation (both P < 0.01). The decrease in LDL lipid peroxides both with HDL and with paraoxonase were concentration dependent. The degree of protection offered by HDL tended to relate to its paraoxonase activity (R = 0.47; P < 0.06). Neither purified paraoxonase nor HDL chelated Cu2+ sufficiently to account for the decrease in LDL oxidation. Purified paraoxonase did not affect LDL oxidation when it had been heat inactivated. Mass transfer of lipid peroxides from LDL to HDL did not explain the protection of LDL against oxidation: the total lipid peroxides accumulating during incubation was decreased both by HDL and by paraoxonase. These results suggest a direct role for HDL in preventing atherosclerosis probably by an enzymic process which prevents the accumulation of lipid peroxides on LDL. Paraoxonase is an example of an enzyme which might possibly be involved.

                Author and article information

                Indian J Nephrol
                Indian Journal of Nephrology
                Medknow Publications (India )
                Jan-Mar 2010
                : 20
                : 1
                : 9-14
                Department of Biochemistry, Kasturba Medical College, Manipal - 576 104, India
                Author notes
                Address for correspondence: Dr. Mungli Prakash, Department of Biochemistry, Kasturba Medical College, Manipal-576 104, India. E-mail: prakashmungli@ 123456yahoo.co.in
                © Indian Journal of Nephrology

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Review Article


                Comment on this article