Paraoxonase Enzyme Activity Is Enhanced by Zinc Supplementation in Hemodialysis Patients Effect of Simvastatin Therapy on Paraoxonase Activity and Related Lipoproteins in Familial Hypercholesterolemic Patients Simvastatin Modulates Expression of the PON1 Gene and Increases Serum Paraoxonase: A Role for Sterol Regulatory Element–Binding Protein-2 A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin. The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant–antioxidant system in patients with dyslipidemia Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol. Clinical and Genetic Association of Serum Paraoxonase and Arylesterase Activities With Cardiovascular Risk Improved fibrinolysis after 1-year treatment with HMG CoA reductase inhibitors in patients with coronary heart disease. Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy. The CHORUS (Cerivastatin in Heart Outcomes in Renal Disease: Understanding Survival) protocol: a double-blind, placebo-controlled trial in patients with esrd. Paraoxonase-1 activity, malondialdehyde and glutathione peroxidase in non-alcoholic fatty liver disease and the effect of atorvastatin. Atorvastatin Preferentially Reduces LDL-Associated Platelet-Activating Factor Acetylhydrolase Activity in Dyslipidemias of Type IIA and Type IIB Effect of the nutritional supplement ALAnerv® on the serum PON1 activity in post-acute stroke patients. Paraoxonase-1 is a major determinant of clopidogrel efficacy Antioxidant effect of atorvastatin is independent of PON1 gene T(–107)C, Q192R and L55M polymorphisms in hypercholesterolaemic patients Arylesterase activity and antioxidant status depend on PON1-Q192R and PON1-L55M polymorphisms in subjects with increased risk of cardiovascular disease consuming walnut-enriched meat.
Background and Aims : Patients on maintenance hemodialysis ( HD ) face an increased risk of atherosclerosis , a crucial problem and the leading cause of cardiovascular morbidity and mortality . This study was design ed to evaluate the effects of zinc supplementation on paraoxonase ( PON ) enzyme activity in patients on HD . Methods : This double-blind r and omized controlled trial was conducted from June 2005 to June 2007 . Sixty HD patients were enrolled and divided into two groups : treatment ( case ) and control . The treatment and control groups were treated with 100 mg/day zinc or placebo , respectively , for 2 months . Serum zinc concentration was measured by atomic absorption spectrophotometry . PON activity  was evaluated by spectrophotometric method . Lipid profile  was determined using commercial kits , and apolipoprotein AI ( Apo-AI ) and B ( Apo-B ) levels were measured by commercial immunoturbidimetric kits . Results : In the case group , there was no significant change in the serum total cholesterol ( TC ) , triglyceride ( TG ) , low-density lipoprotein ( LDL ) , and Apo-B levels , while the serum levels of high-density lipoprotein ( HDL ) , Apo-AI , and PON activity were significantly increased ( p = 0.02 ) . In the control group , although significant increases were observed in the serum levels of TC , TG , and Apo-B ( p = 0.009 , 0.019 , and 0.001 , respectively ) , the serum PON activity was significantly decreased ( p = 0.025 ) and the serum levels of HDL , LDL , and Apo-AI were not changed . At the end of intervention period , the serum level of Apo-AI and PON activity were significantly higher in the case group . Conclusions : Zinc supplementation increased both the activity of PON and the serum level of Apo-AI in the HD patients Human paraoxonase ( PON1 ) is a calcium-dependent esterase closely associated with high density lipoprotein (HDL)-containing apolipoprotein AI ( apoAI ) , which has been shown to confer antioxidant properties to HDL . PON1 has been recently implicated in the pathogenesis of atherosclerosis . Low PON1 activities have been found in familial hypercholesterolemia ( FH ) and diabetes mellitus . We have undertaken a study of the effect of the lipid-lowering drug simvastatin on serum PON1 activity ( in relation to paraoxon and arylesterase activity ) , on apoAI-containing and apolipoprotein B (apoB)-containing lipoproteins , and on lipid peroxide concentrations in 64 ( 39 women and 25 men ) unrelated FH patients . We have also analyzed the influence of the PON1 - 192 and PON1 - 55 genetic polymorphisms on the response of PON1 activity to simvastatin therapy . A venous blood sample for a baseline analysis and another after 4 months of simvastatin therapy at a dosage of 20 mg per day were taken . The major effect of simvastatin on lipid traits was to decrease serum cholesterol , low density lipoprotein ( LDL ) cholesterol , and lipid peroxide concentrations by 19.9 % , 26.3 % , and 37.3 % , respectively . There was also a significant decrease in serum apoB , LDL apoB , and triglyceride concentrations ( 20.5 % , 21.1 % , and 15.6 % , respectively ) . Conversely , simvastatin had no significant influence on very low density lipoprotein – lipid content , HDL cholesterol , apoAI concentrations , and lipoprotein AI and AI : AII particles . Remarkably , serum PON1 activity toward paraoxon significantly increased during treatment with simvastatin ( 168.7±100.3 U/L before therapy versus 189.5±116.5 U/L after therapy , P = 0.005 ) . Arylesterase activity displayed only a nonsignificant trend to increase after therapy . Whereas PON1 activity levels were significantly lower in FH patients  before simvastatin therapy compared with those of 124 normolipidemic subjects ( 168.7±100.3 versus 207.6±125.2 U/L , respectively;P < 0.05 ) , this difference disappeared after simvastatin therapy . After simvastatin therapy , a significantly negative correlation between PON1 activity and lipid peroxide concentration was observed ( r = −0.35 , P = 0.028 ) . The latter also strongly correlated with LDL cholesterol concentration ( r = 0.64 , P < 0.001 ) . Serum PON1 activity levels were significantly lower in the low-activity PON1 - 192 QQ and PON1 - 55 M carriers than in R carriers and in LL carriers , respectively . No significant differences were found in the therapeutic response of PON1 activity between genotype groups ( 8.5 % and 11.1 % increase for QQ homozygous and R-carrier FH patients , respectively , and 12.7 % and 9.5 % increase for LL homozygotes and M carriers , respectively ) . We conclude that simvastatin may have important antioxidant properties through increasing serum PON1 activity , perhaps as a consequence of reducing oxidative stress , by a mechanism independent of apoAI-containing lipoprotein concentration and without the influence of PON1 - 192 and PON1 - 55 genetic polymorphisms . Further studies are clearly warranted to clarify the precise mechanism by which simvastatin therapy is associated with increased PON1 activity Background —The HDL-associated enzyme paraoxonase protects LDLs from oxidative stress . 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ( statins ) appear to favorably influence the atherosclerotic process by different mechanisms . The present study examined the influence of simvastatin on paraoxonase expression and serum paraoxonase levels . Methods and Results —Simvastatin upregulated in a dose-dependent manner the activity of the promoter of the paraoxonase gene in expression cassettes transfected into HepG2 cells . Upregulation could be blocked by mevalonate and other intermediates of the cholesterol biosynthetic pathway . Simvastatin increased nuclear factors , notably sterol regulatory element – binding protein-2 , capable of binding to the paraoxonase promoter ; this was also blocked by mevalonate . Sterol regulatory element – binding protein-2 upregulated promoter activity in vitro . Patients treated with statin  showed a significant increase in serum concentrations and activities of paraoxonase . Conclusions —The data indicate that simvastatin can modulate expression in vitro of the antioxidant enzyme paraoxonase and is associated with increased serum paraoxonase concentration and activity . It is consistent with effects of simvastatin treatment , which have the potential to influence beneficially antiatherogenic mechanisms at the HDL level . The study provides evidence for 1 molecular mechanism by which paraoxonase gene expression could be regulated Human serum paraoxonase ( PON1 ) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein ( LDL ) . PON1 has a Glu to Arg polymorphism at codon 192 ( CGA-->CAA ) which is design ated R/Q192 . The R/Q192 polymorphism has been associated with coronary artery disease ( CAD ) in several , but not all , case-control studies . We prospect ively studied the association of the Q/R192 genotypes with the severity , progression and regression of CAD , plasma lipid levels , clinical events and response to treatment with fluvastatin in a well-characterized cohort . Genotypes were determined by polymerase chain reaction ( PCR ) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study ( LCAS ) .  Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following r and omization to fluvastatin or placebo . A total of 177 ( 50 % ) , 142 ( 40 % ) and 37 ( 10 % ) subjects had Q/Q , Q/R and R/R genotypes , respectively . Baseline and final plasma levels of HDL , LDL , triglyceride and other lipoproteins , lesion-specific minimum lumen diameters ( MLD ) , mean MLD , number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes . There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD . The Q/R192 variants of PON1 are not associated with severity , progression or regression of coronary atherosclerosis , plasma lipid levels , clinical events , or response to treatment with fluvastatin .  Thus , the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population Background Atorvastatin , an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase , which is used for lipid-lowering therapy , is an effective statin modulating process involved in atherosclerosis . Paraoxonase ( PON ) associated with high-density lipoprotein ( HDL ) has been postulated to have a role in protecting low-density lipoprotein ( LDL ) against oxidative modification . Oxidation of serum LDL is an important early step in the development of atherosclerosis and auto-antibodies against oxidized LDL ( AuAb-oxLDL ) reflect in-vivo LDL oxidation . Design and methods To examine the effect of atorvastatin ( 10 mg/day ) therapy on PON activity in serum and HDL , the study group included 40 patients with dyslipidemia ( 19 women and 21 men ) , 25 of whom had hypercholesterolemia and of 15 of whom had mixed-type hyperlipidemia . By taking blood sample s from the patients , levels of serum lipids , lipid peroxidation product as malondialdehyde ( MDA ) , total antioxidant status ( TAS ) and AuAb-oxLDL and the activities of PON in serum and isolated HDL were determined . Results The mean levels of total cholesterol , triglyceride , LDL-cholesterol , MDA and AuAb-oxLDL were decreased while HDL-cholesterol and TAS were increased significantly after lipid-lowering therapy in patients with dyslipidemia . On the other h and , PON activities in serum and HDL were increased significantly . The percentage increase in serum PON activity was associated significantly with the percentage decrease in serum AuAb-oxLDL ( r=−0.32 , P=0.047 ) and that of HDL PON activity was associated with the percentage increase in HDL-cholesterol level after atorvastatin therapy ( r=0.52 , P=0.001 ) . The therapy was more effective in increasing PON activity in patients with HDL levels above 35 mg/dl . Conclusion It was concluded that atorvastatin therapy in dyslipidemic patients decreases the level of oxidative stress and increases PON activity , especially in patients with HDL levels above 35 mg/dl Paraoxonase ( PON ) is an enzyme carried by high-density lipoprotein cholesterol ( HDL-C ) . Two gene polymorphisms leading to amino acid substitutions of methionine for leucine at position 55 ( M/L55 ) and arginine for glutamine at position 192 ( R/Q192 ) modulate the activity of the enzyme and possibly also lipid and apolipoprotein concentrations . Our purpose was to examine the effect of the PON genotype on HDL-C and apolipoprotein AI ( apo AI ) responses to pravastatin treatment . Fifty-one mildly hypercholesterolemic male subjects ( mean age 35 + /- 4 years ) were enrolled by this prospect i ve , r and omized , double-blind study . Lipid concentrations were measured at baseline and after 6 months of pravastatin ( n = 25 ) or placebo ( n = 26 ) therapy . Low active ( MM , ML or QQ ) and high active ( LL or RQ , RR ) PON genotype groups were related to lipid and apolipoprotein concentration changes . Pravastatin increased the apo AI concentration 12 % ( P = 0.017 , RANOVA ) and tended to increase the HDL-C concentration ( P = 0.095 , RANOVA ) in R allele carriers but not in QQ homozygotes . Significant predictors of the change in apo AI concentration during pravastatin treatment were R/Q192 genotype ( P = 0.002 ) , apo AI concentration at baseline ( P = 0.002 ) and M/L55 genotype ( P = 0.042 ) . Correspondingly , R/Q192 ( P = 0.009 ) and M/L55 ( P = 0.050 ) genotypes were the statistically significant determinants of HDL-C concentration change . The PON genotype thus modifies the effect of pravastatin on serum HDL-C and apo AI concentrations . This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concentration Objective —Diminished serum paraoxonase and arylesterase activities ( measures of paraoxonase-1 [ PON-1 ] function ) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk . The clinical prognostic use of measuring distinct PON-1 activities has not been established , and the genetic determinants of PON-1 activities are not known . Methods and Results —We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospect ively followed for major adverse cardiovascular events ( MACE= death , myocardial infa rct ion , stroke ) over 3 years . Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE , with arylesterase activity showing greatest prognostic value ( quartile 4 versus quartile 1 ; hazard ratio 2.63 ; 95 % CI , 1.97–3.50 ; P<0.01 ) . Arylesterase remained significant after adjusting for traditional risk factors , C-reactive protein , and creatinine clearance ( hazard ratio , 2.20 ; 95 % CI , 1.60–3.02 ; P<0.01 ) , predicted future development of MACE in both primary and secondary prevention population s , and reclassified risk categories incrementally to traditional clinical variables . A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase ( 1.18 × 10 - 303 ) or arylesterase ( 4.99 × 10−116 ) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort ( n=2136 ) or history of either coronary artery disease or myocardial infa rct ion in the Coronary Artery Disease Genome-Wide Replication and Meta- Analysis consortium ( n≈80 000 subjects ) . Conclusion —Diminished serum arylesterase activity , but not the genetic determinants of PON-1 functional measures , provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE The study was aim ed to investigate the effect of two different statins on the levels of haemostatic variables reflecting procoagulant and fibrinolytic activity in patients with coronary heart disease ( CHD ) , with the hypothesis that statins might beneficially modify these levels . Fifty-eight patients were r and omized to treatment with atorvastatin ( n=28 ) or simvastatin  ( n=30 ) for 1 year . The starting dose in both groups was 20 mg/day . Fasting blood sample s were collected before and after 12-month treatment for determinations of fibrinogen , prothrombin fragment 1 + 2 ( F1 + 2 ) , plasma D-dimer , soluble tissue factor , tissue plasminogen activator ( tPA ) antigen , tPA activity , plasminogen activator inhibitor type-1 activity ( PAI-1 activity ) and serum D-dimer as a global test of fibrinolytic activity . In the total population , improved fibrinolytic activity was observed after 1 year with increased levels of serum D-dimer ( P=.001 ) and tPA activity ( P=.024 ) and a reduction in tPA antigen ( P=.048 ) . No statistically significant changes were observed in any of the measured coagulation variables . Separately examined , an improved fibrinolytic profile was seen in the atorvastatin group with a significant increase in serum D-dimer ( P=.005 ) , a borderline increase in tPA activity ( P=.083 ) and a borderline reduction in tPA antigen ( P=.069 ) . Within the simvastatin group , a reduction in prothrombin F1 + 2 was observed ( P=.038 ) . The differences in changes between the groups were statistically significant only for global fibrinolysis ( serum D-dimer , P=.046 ) . In conclusion , an improved fibrinolytic profile was observed after statin treatment , most pronounced with atorvastatin . The results indicate that the drugs promote a profibrinolytic profile , and may in part explain the benefit of statin treatment rendered in the prevention of CHD SUMMARY Objective : High-density lipoprotein (HDL)-associated paraoxonase ( PON ) activity may play an important role in the inhibition of low-density lipoprotein ( LDL ) oxidation . Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease . The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia . Research design and methods : A prospect i ve , non-blinded , single-group , cross-over , comparative trial was performed . Following an 8-week dietary run-in period , 49 patients ( 23 men and 26 women , mean age : 59.8 ± 7.9 years ) with Fredrickson type IIa . and IIb . hyperlipoproteinaemias were r and omized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months . Following an 8-week washout period , patients were crossed-over to receive the other drug for a further 3 months . Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate . Results : Simvastatin treatment significantly reduced serum cholesterol , LDL-cholesterol ( LDL-C ) and apolipoprotein ( apo ) B levels ( p < 0.001 ) . Atorvastatin had a more pronounced cholesterol , LDL-C- and apo B-lowering effect ( p < 0.001 ) compared with simvastatin . Both statins also significantly reduced serum triglyceride levels  ( p < 0.01 ) . Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol ( HDL-C ) and apo A1 . HDL-associated PON activity did not change significantly after simvastatin therapy , but significantly increased after atorvastatin treatment ( p < 0.05 ) . Conclusions : Short-term administration of simvastatin did not increase PON activity  . Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme ( PON1 ) activity in type 2 diabetic Egyptian patients with or without nephropathy . The present study was carried out on the following groups : control group , which consisted of 30 healthy persons ; Group I , which consisted of 20 type 2 diabetic patients without nephropathy ; and Group II , which consisted of 20 type 2 diabetic patients with nephropathy . All the patients selected were under an antidiabetic regimen of insulin  , and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies . Twenty-two patients ( 15 without nephropathy and seven with nephropathy ) received atorvastatin in individually adjusted oral dosage ( range 10 - 20 mg ) once per day for 12 weeks . All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity , malondialdehyde ( MDA ) , glutathione reductase activity , fasting glucose , total cholesterol , triglycerides , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) , urea , and creatinine . Urine sample s were collected for determination of proteinuria . The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group , with significant difference in their levels between Group II and Group I. MDA , total cholesterol , and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group . Urea , creatinine , and proteinuria levels showed significant increase in Group II when compared to the control group and Group I , with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity , and serum levels of MDA and glutathione reductase activity were significantly decreased and increased , respectively . Also , total cholesterol , triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels . There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level . Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period . PON1 activity showed a significant negative correlation with glucose and LDL , and a significant positive correlation with HDL in all the studied groups . It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia , but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy . More specifically , restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy . Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-mediated lowering of serum cholesterol has been associated with a significant reduction in cardiovascular morbidity and mortality . Recent studies suggest that additional non-lipid lowering effects ( eg , endothelial stabilization , anti-inflammatory , antithrombogenic ) may be important in modulating their effectiveness . Dyslipidemia is common in end-stage renal disease ( ESRD ) , and hemodialysis patients have increased cardiovascular morbidity and mortality . Cerivastatin , a new statin with powerful low-density lipoprotein-cholesterol ( LDL-C ) lowering capabilities , possesses some unique non-LDL-C-mediated properties that may contribute to a reduction of coronary events in the patient with ESRD . The primary objective of this multicenter multinational study of 1,054 hemodialysis patients is to compare 2 years of treatment with cerivastatin ( 0.4 mg/d ) versus placebo on the composite clinical event rate of myocardial infa rct ion , sudden cardiac death , ischemic stroke , and the need for coronary arterial bypass graft ( CABG ) or percutaneous transluminal coronary angioplasty ( PTCA ) procedures in these patients . Changes in lipids , inflammatory proteins including heat stable C-reactive protein ( hsCRP ) , interleukin-6 ( IL-6 ) , oncostatin-M , intracellular adhesion molecule-1 ( ICAM-1 ) and monocyte-chemoattractant protein-1 ( MCP-1 ) , as well as markers of cardiac muscle pathology , such as troponin I and troponin T , will be assessed in a subset of patients . This study is the first of its kind to assess the effect of a statin on the reduction of cardiovascular morbidity and mortality in an incident hemodialysis population . It will determine whether treatment with cerivastatin can effectively reduce the significant cardiovascular morbidity and mortality BACKGROUND AND STUDY AIMS The prevalence of non-alcoholic fatty liver disease ( NAFLD ) appears to be increasing . The aim of the present study was to investigate the relationship between hepatic antioxidant paraoxonase 1 ( PON1 ) activity , lipid peroxidation and antioxidant enzymes in patients with NAFLD and the effect of atorvastatin . PATIENTS AND METHODS This study was conducted on 50 patients with NAFLD and 20 normal subjects matched for age and sex . All of them were subjected to the following investigations : abdominal ultrasonography , serum PON1 activity level , liver function tests , serum lipid profile , fasting and postpr and ial blood glucose and serum levels of malondialdehyde ( MDA ) and glutathione peroxidase ( GP ) .  NAFLD patients were further r and omly classified into two groups ( 25 patients each ) , groups Ia and Ib . Only group Ia received atorvastatin 40 mg tablet for 8months . RESULTS Obesity , dyslipidaemia and impaired glucose tolerance were prevalent in group I. There was a significant decrease in serum PON1 activity with a significant increase in MDA and GP activity ( i.e. , there is a significant increase in lipid peroxidation rate ) in group I compared with group II . After atorvastatin therapy , there was a significant increase in serum PNO1 activity and significant decrease in serum MDA levels . CONCLUSION Patients with NAFLD show enhanced oxidative stress which may lead to non-alcoholic steatohepatitis ( NASH ) . Reduced PON1 activity and increased MDA could be considered a biochemical marker for lipid peroxidation , which require follow-up in patients with NAFLD . Atorvastatin may have a role in prevention of , or delay , the transformation of liver steatosis into NASH Human plasma platelet-activating factor acetylhydrolase ( PAF-AH ) is a phospholipase A2 that is primarily associated with low density lipoprotein ( LDL ) . PAF-AH activity has also been found in high density lipoprotein ( HDL ) , although it has recently been indicated that there is no PAF-AH protein in HDL . Plasma paraoxonase 1 ( PON1 ) is an HDL-associated esterase , which also exhibits PAF-AH – like activity . The effect of atorvastatin ( 20 mg per day for 4 months ) on PAF-AH and PON1 activities in patients with dyslipidemia of type IIA ( n=55 ) or type IIB ( n=21 ) was studied . In both patient groups , atorvastatin significantly reduced plasma PAF-AH activity because of the decrease in LDL plasma levels and the preferential decrease in PAF-AH activity on dense LDL subfractions ( LDL-4 and LDL-5 ) . Drug therapy did not affect HDL-associated PAF-AH activity or serum PON1 activities toward paraoxon and phenylacetate in either patient group . However , because of the reduction in LDL cholesterol levels , the ratios of HDL-associated PAF-AH and serum PON1 activities to LDL cholesterol levels were significantly increased after drug administration . The reduction of the LDL-associated PAF-AH activity and the elevation in the ratios of HDL-associated PAF-AH and PON1 activities to LDL plasma levels may represent a new dimension in the antiatherogenic effect of atorvastatin BACKGROUND Paraoxonase-1 ( PON1 ) is one of the HDL-associated proteins which contributes to the antioxidant properties of these lipoproteins . The aim of this pilot study was to evaluate the effect of the nutritional supplement ALAnerv ® on serum PON1 activity in post-acute stroke patients undergoing rehabilitation . METHODS We enrolled 28 post-acute stroke patients and r and omly divided them into ( - ) ALA or ( + ) ALA study groups . All the patients underwent the same rehabilitation program and received comparable st and ard medications . Moreover , ( + ) ALA patients received ALAnerv ® for two weeks ( 2 pills/day ) . The serum PON1 activity was assessed on blood sample s taken at the admission and at the discharge moments , respectively . We used paraoxon ( paraoxonase activity , PONA ) , phenyl acetate ( arylesterase activity , ARYLA ) and dihydrocoumarin ( lactonase activity , LACTA ) as substrates , the latter activity being regarded as physiologically relevant . A control group of 14 apparently healthy subjects was also created . RESULTS In the ( + ) ALA group , LACTA significantly increased during the study period ( 17.6 ± 3.2 vs. 27.6 ± 3.5 , p = 0.002 ) . Moreover , the percentage of LACTA variation between ( - ) ALA and ( + ) ALA groups during the study was also statistically different ( -11.7 ± 6.9 % vs. + 95.1 ± 29.7 % , p < 0.0001 ) . CONCLUSIONS These preliminary results suggest that ALA nerv ® could contribute to the improvement of the physiologically relevant LACTA of PON1 in post-acute stroke patients , enabling this enzyme to contribute to the redox correction . Also , this study raises the question about the effect of a longer treatment period over the other enzymatic activities of serum PON1 Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite . The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors , but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear . Using in vitro metabolomic profiling techniques , we identified paraoxonase-1 ( PON1 ) as the crucial enzyme for clopidogrel bioactivation , with its common Q192R polymorphism determining the rate of active metabolite formation . We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy .  PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis , lower PON1 plasma activity , lower plasma concentrations of active metabolite and lower platelet inhibition . Thus , we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel . These findings have therapeutic implication s and may be exploited to prospect ively assess the clinical efficacy of clopidogrel ABSTRACT Background : Serum paraoxonase ( PON1 ) , a high density lipoprotein (HDL)-bound antioxidant enzyme , plays a role in atherosclerosis . An increase in PON1 activity has been reported following statin treatment . Objective : In the present study the following factors were evaluated : the influence of PON1 gene Q192R , L55 M and T(–107)C polymorphisms on the response of LDL oxidisability and PON1 activity to atorvastatin treatment . Research design and methods : 205 Sicilian subjects with primary hypercholesterolaemia ( HCh ) and 69 healthy subjects as controls were concurrently enrolled . Hypercholesterolaemic patients were r and omly divided into two groups : an atorvastatin group ( 10 mg/day atorvastatin ) and a placebo group .  Lipid profile , markers of LDL resistance to in vitro oxidation ( lag-phase , oxidation rate and thiobarbituric acid-reactive substances ) , vitamin E content in LDL , PON1 activity and genotypes in both HCh and control subjects were determined at baseline . The same parameters were measured again after 3 weeks of treatment in both the atorvastatin and placebo groups . Results : HCh subjects showed significantly lower LDL resistance to oxidation , vitamin E content and PON1 activity levels than controls . A strong association was found among PON1 T(–107)C genotypes , LDL susceptibility to oxidation , vitamin E content and PON1 activity . After treatment , the atorvastatin group displayed a significant decrease in total cholesterol , LDL-cholesterol levels , and LDL susceptibility to oxidation , and an increase in vitamin E content and PON1 activity , compared with baseline values . Unlike PON1 activity levels , no difference among PON1 gene polymorphisms and reduction in markers of LDL oxidisability was observed . Conclusions : These results show , for the first time , that atorvastatin is able to improve the resistance to LDL oxidation independently of PON1 gene polymorphism Human paraoxonase ( PON1 ) exists in 2 major polymorphic forms and has been shown to protect LDL and HDL against oxidation . The aim of this study was to assess the differences between subjects at increased risk of cardiovascular disease ( CVD ) , taking into account the effects of PON1-Q192R and PON1-L55 M polymorphisms on 1 ) basal serum arylesterase activity , lipid peroxidation ( LPO ) , and LDL-cholesterol ( LDL-C ) , HDL-C , total cholesterol ( TC ) , and oxidized-LDL ( ox-LDL ) concentrations ; 2 ) the relations between arylesterase activity and lipid variables ; and 3 ) the effect of walnut-enriched meat ( WM ) consumption on arylesterase activity and lipid variables .  Twenty-three Caucasians at increased risk of CVD were r and omly assigned to diet order groups in a crossover , nonblinded , placebo-controlled trial , consisting of two 5-wk experimental periods [ WM and control meat ( CM ) ] . Significant PON1-L55 M x PON1-Q192R interactions affected basal serum HDL-C ( P = 0.019 ) , LDL-C ( P = 0.028 ) and TC ( P = 0.022 ) and tended to affect arylesterase activity ( P = 0.083 ) . Basal arylesterase activity was positively correlated with basal HDL-C ( r = 0.53 ; P < 0.05 ) and TC ( r = 0.43 ; P < 0.05 ) and negatively correlated with LPO ( r = -0.70 ; P < 0.01 ) and the ox-LDL : LDL ratio ( r = -0.63 ; P < 0.01 ) . WM decreased arylesterase activity in PON1 - 55 M carriers ( P = 0.012 ) but not in PON1-L55 individuals , and decreased LPO concentrations in PON1 - 192R carriers ( P = 0.031 ) but not in PON1-Q192 subjects . To conclude , serum TC , HDL-C , and LDL-C concentrations and arylesterase activity depend on the interaction of PON1-L55 M and PON1-Q192R polymorphisms . However , the PON1-Q192R polymorphism is more closely related to antioxidant status . Both polymorphisms modulate the effect of WM consumption on CVD biomarkers
RESULTS Meta- analysis suggested that statin therapy is associated with a significant elevation of PON1 paraoxonase and arylesterase activities , but not PON1 protein concentration .
The PON1-enhancing effects of statins were robust in the sensitivity analyses and were independent of statin dose , treatment duration and changes in plasma low-density lipoprotein cholesterol concentration .
CONCLUSION The increase of paraoxonase and arylesterase activities with statins is a pleiotropic lipid-independent clinical benefit that may partly explain the putative effects of statins in preventing cardiovascular outcomes
BACKGROUND Decreased activity of the enzyme paraoxonase-1 ( PON1 ) has been demonstrated in cardiovascular diseases .
Statins , the forefront of pharmacotherapy for dyslipidemia , have been shown to enhance PON1 activity but clinical findings have not been conclusive .
OBJECTIVE To systematic ally review the clinical findings on the impact of statin therapy on PON1 status ( protein concentrations and activities of paraoxonase and arylesterase ) and calculate an effect size for the mentioned effects through meta- analysis of available data .