Activity of paraoxonase 1 (PON1) and its relationship to markers of lipoprotein oxidation in healthy Slovaks

Low-density lipoproteins (LDLs), when modified by free radicals derived from artery wall cells, induce atherosclerosis. In contrast to oxidized LDL (ox-LDL), high-density lipoproteins (HDLs) are able to prevent atherosclerosis through a protein with antioxidant properties, paraoxonase 1 (PON1). The purpose of this study was to explore the association between the activity of HDL-associated PON1 and circulating ox-LDL as well as to investigate the relationship between ox-LDL and parameters of lipid profile in thirty Slovaks aged 21-73 years because recent studies have presented controversial results concerning PON1 and its role in LDL oxidation. For determination of circulating ox-LDL sandwich ELISA was used and other lipid parameters were determined by routine laboratory analyses. PON1 activities were assayed by two synthetic substrates - paraoxon and phenyl acetate. Lipid peroxides were determined spectrophotometrically. Of the lipid parameters examined, ox-LDL level correlated positively with total (P < 0.0001) and LDL-cholesterol (P < 0.001). Triacylglycerols (TAG) (P < 0.001), lipid peroxides (P < 0.01) and atherogenic index (AI = total cholesterol/HDL) (P < 0.0001) were also strongly correlated with ox-LDL. No inverse relationships were observed between ox-LDL and HDL-cholesterol or arylesterase/paraoxonase activities of PON1. Furthermore, it was found that ox-LDL (P < 0.01) and lipid peroxides (P < 0.05) were significantly higher in men than in women. PON1 arylesterase activity was marginally affected by sex. The results of this study suggest that the anti-atherogenic properties of HDLs are not directly related to their total concentration and that PON1 activity determined towards synthetic compounds (paraoxon and phenyl acetate) reflects no association with markers of oxidative stress. Furthermore, it follows from our results that men are more susceptible to developing atherosclerosis compared to women.     

Paraoxonase 1 (PON1) and its relationship to lipid variables, age and gender in healthy volunteers

Recent studies implied that low-density lipoprotein (LDL) modified predominantly by oxidation or glycation, significantly contributes to the formation of atherosclerotic lesions. In contrast to oxidized LDL (ox-LDL), high-density lipoprotein (HDL) is able to prevent accumulation of ox-LDL in arterial walls. This antiatherogenic property of HDL is attributed in part to several enzymes associated with the lipoprotein, including HDL-associated paraoxonase 1 (PON1). In this study we analyzed PON1 arylesterase/paraoxonase activities in relation to serum lipid profile, gender and age in thirty clinically healthy Slovak volunteers. Our results showed that PON1 arylesterase and paraoxonase activities were lower in citrated plasma than in serum by 16.6% and 27.3%, respectively. Among serum lipoproteins, only HDL-cholesterol level showed significant positive correlation with PON1 arylesterase activity (p = 0.042). Likewise, we found a significant relationship between atherogenic index (AI = total cholesterol/HDL-cholesterol) and PON1 arylesterase activity (p = 0.023). No significant correlation could be demonstrated between PON1 paraoxonase activity and serum lipid profile, age or gender. Furthermore, it was found that PON1 paraoxonase/arylesterase activities were higher in women compared with both investigated activities in men, but these differences were not statistically significant. These results confirmed a positive correlation between HDL-cholesterol and PON1 arylesterase activity. Moreover, it was found out that PON1 paraoxonase activity is not influenced either by gender or by age. PON1 arylesterase activity was however affected by gender to a limited extent.     

Effect of single bout of maximal exercise on plasma antioxidant status and paraoxonase activity in young sportsmen

The purpose of this study was to elucidate the participation of plasma PON1 (paraoxonase activity [PON] and arylesterase activity [ARE]) in antioxidant defense in response to a single bout of maximal exercise. PON, ARE, lipid profile, lipid peroxidation (thiobarbituric acid reactive substances [TBARS]), total antioxidant status (ferric reducing ability of plasma [FRAP]), concentration of uric acid [UA], and total bilirubin (TBil) were determined in the plasma before, at the bout and 2 h after maximal exercise on a treadmill in young sportsmen. Chosen physiological parameters also were controlled during maximal exercise. Following maximal exercise, the unaltered level of TBARS and increased FRAP were registered. ARE increment was the highest (37.6%) of all measured variables but lasted for a short time. UA increment was lower than ARE but long-lasting and correlated with FRAP. PON activity increment was associated with the combined effect of body weight, lean, body mass index (BMI) and basal metabolic rate (BMR). We conclude that PON1 is a co-factor of the first line of antioxidant defense during maximal exercise. Its activity is associated with body composition and not the physical fitness of the subjects.     

Levels of paraoxonase and arylesterase activities and malondialdehyde in workers exposed to ionizing radiation

We examined levels of malondialdehyde (MDA) (an end-product of lipid peroxidation) and paraoxonase (PON1) (an antioxidant enzyme) activity and PON1 phenotypes in people who were exposed to ionizing radiation for different time periods and doses. A total of 78 individuals (mean age 34 +/- 7 years) were included in the study. Fifty-one of them were radiology workers whereas the control group was composed of 27 healthy volunteers who had never worked in a radiology-related job. Paraoxon was used as substrate for measurement of PON1 activity levels (basal and NaCl-stimulated). Phenylacetate was used as substrate for measurement of arylesterase activity levels. Cumulative levels of serum NaCl-stimulated PON1/arylesterase activities were utilized for phenotypic differentiation. In radiology workers, three different phenotypes were determined based on paraoxonase/arylesterase ratio. The ratios were 1.09 +/- 0.30 for AA (homozygote low activity); 2.91 +/- 1.07 for AB (heterozygote activity) and 4.97 +/- 1.21 for BB (homozygote high activity). There was a statistically meaningful negative correlation between serum MDA levels and PON1 activity levels in all phenotypes (p < 0.05). PON1 activity levels were found to be 25-35% lower in people who were exposed to long-term ( > 5 years) radiation compared to controls. There was no statistically significant correlation between serum arylesterase activity and MDA levels in these subjects (r = -0.185, p > 0.05). PON1 activity levels were decreased whereas serum MDA levels were increased in individuals exposed to radiation for a long period. PON phenotypes of people employed in jobs which expose them to radiation should be determined and based on these findings they should be advised to avoid risk factors inducing oxidative stress, such as smoking, and to consume foods rich in vitamins and trace elements to increase their antioxidant capacity.     

Serum lipid profile paraoxonase and arylesterase activities in psoriasis

Psoriasis is a common chronic and recurrent inflammatory skin disease with unknown etiology that has been associated with abnormal plasma lipid metabolism and oxidative stress. There are controversial results in the previous studies investigating oxidant/antioxidant systems in psoriasis. The aim of this work was to evaluate dyslipidemia, oxidative stress, total antioxidant capacity and serum paraoxonase (PON1) and arylesterase (ARE) activities in psoriasis, and to look for a correlation between these parameters and lesion percentage in psoriasis. Thirty psoriatic patients and twenty three sex‐ and agematched healthy volunteers were included in the study. From blood samples, lipid profile, malondialdehyde (MDA) levels, total antioxidant capacity (TAO), serum PON1 and ARE activities were determined. No significant differences between the patients and controls were found in terms of total cholesterol, triacylglycerol (TAG), HDL‐cholesterol, LDL‐cholesterol, VLDL‐cholesterol, MDA and TAO levels. Serum PON1 and sodium‐stimulated PON1 activities (p < 0.05) and ARE activity (p < 0.01) were found significantly higher in the patients than in the controls. There was not any significant correlation between lesion percentage and the parameters studied. Copyright © 2009 John Wiley & Sons, Ltd.     

Preferable stimulation of PON1 arylesterase activity by phosphatidylcholines with unsaturated acyl chains or oxidized acyl chains at sn-2 position

To examine the effect of phospholipids on PON1 activities, purified PON1 was exposed to phospholipids prior to the determination of arylesterase and paraoxonase activities. Phosphatidylcholines with saturated acyl chains (C10-C16) showed a stimulation of both activities, chain length-dependent, with a greater stimulation of arylesterase activity, suggesting the implication of lipid bilayer in the stimulatory action. Such a preferable stimulation of arylesterase activity was more remarkable with phosphatidylcholines with polyunsaturated acyl chains or oxidized chains at sn-2 position, implying that the packing degree of acyl chain may be also important for the preferable stimulation of arylesterase activity. Separately, 1-palmitoyl-lysoPC also stimulated arylesterase activity preferably, indicating that the micellar formation of lipids around PON1 also contributes to the stimulatory action. Additionally, phosphatidylglycerols slightly enhanced arylesterase activity, but not paraoxonase activity. In contrast, phosphatidylserine and phosphatidic acid (> or =0.1 mM) inhibited both activities Further, such a preferable stimulation of arylesterase activity by phosphatidylcholines was also reproduced with VLDL-bound PON1, although to a less extent. These data indicate that phosphatidylcholines with polyunsaturated acyl chains or oxidized chain, or lysophosphatidylcholine cause a preferable stimulation of arylesterase activity, thereby contributing to the decrease in the ratio of paraoxonase activity to arylesterase activity.     

Preferable stimulation of PON1 arylesterase activity by phosphatidylcholines with unsaturated acyl chains or oxidized acyl chains at sn-2 position

To examine the effect of phospholipids on PON1 activities, purified PON1 was exposed to phospholipids prior to the determination of arylesterase and paraoxonase activities. Phosphatidylcholines with saturated acyl chains (C10-C16) showed a stimulation of both activities, chain length-dependent, with a greater stimulation of arylesterase activity, suggesting the implication of lipid bilayer in the stimulatory action. Such a preferable stimulation of arylesterase activity was more remarkable with phosphatidylcholines with polyunsaturated acyl chains or oxidized chains at sn-2 position, implying that the packing degree of acyl chain may be also important for the preferable stimulation of arylesterase activity. Separately, 1-palmitoyl-lysoPC also stimulated arylesterase activity preferably, indicating that the micellar formation of lipids around PON1 also contributes to the stimulatory action. Additionally, phosphatidylglycerols slightly enhanced arylesterase activity, but not paraoxonase activity. In contrast, phosphatidylserine and phosphatidic acid (≥0.1 mM) inhibited both activities Further, such a preferable stimulation of arylesterase activity by phosphatidylcholines was also reproduced with VLDL-bound PON1, although to a less extent. These data indicate that phosphatidylcholines with polyunsaturated acyl chains or oxidized chain, or lysophosphatidylcholine cause a preferable stimulation of arylesterase activity, thereby contributing to the decrease in the ratio of paraoxonase activity to arylesterase activity.     

Serum paraoxonase and arylesterase activities in patients with chronic otitis media

Objectives: Paraoxonase-1 (PON1) prevents oxidative stress by inhibiting the oxidation of cell membrane lipids by the reactive oxygen species that form during acute and chronic inflammation. The aim of this study was to investigate serum PON1 activity and oxidative stress in patients with chronic otitis media (COM).

Methods: Fifty consecutive patients with COM and 55 controls were enrolled in the present study. The patients were divided into two groups according to the presence of cholesteatoma. The serum PON1 arylesterase activities and lipid hydroperoxide (LOOH) levels were determined.

Results: Serum paraoxonase and arylesterase activities were significantly lower in the COM patients than in the controls (P < 0.001 for all comparisons), whereas the LOOH levels were significantly higher (P < 0.001).

Discussion: These results indicated that a lower level of PON1 activity was associated with an oxidant–antioxidant imbalance. In addition, decreased PON1 activity may play an important role in the pathophysiology of COM.     

Paraoxonase and arylesterase activities in fibromyalgia

We aimed to evaluate the association of serum paraoxonase and arylesterase activities and oxidative/antioxidative status in patients with fibromyalgia. Forty-two patients with fibromyalgia and 53 healthy controls were included in the study. Serum paraoxonase and arylesterase activities were measured spectrophotometrically. Oxidative and antioxidative status were evaluated by measuring serum lipid hydroperoxide (LOOH) levels, total antioxidant status (TAS) and free sulfhydryl groups (-SH = total thiol). Lipid parameters were determined by routine laboratory methods. Serum paraoxonase and arylesterase activities, and TAS were lower in patients with fibromyalgia than in controls (P < 0.001, for all), and the -SH level was also lower in the patient group (P = 0.03). LOOH levels were higher in the patient group than in controls (P = 0.01). Our results suggest that patients with fibromyalgia were exposed to oxidative stress, and paraoxonase and arylesterase activities were decreased in these patients. Patients with fibromyalgia might be prone to development of atherosclerosis with reduced paraoxonase and arylesterase activities.     

Serum Paraoxonase and Arylesterase Activities and Oxidative Stress Levels in Patients with SSRI Intoxication

Oxidative stress is a critical route of damage in various psychological stress-induced disorders, such as depression. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with selective serotonin reuptake inhibitor (SSRI) intoxication. A total of 11 patients with SSRI intoxication and 20 healthy controls were enrolled. The serum total antioxidant capacity (TAC) and malondialdehyde (MDA) levels, as well as the paraoxonase and arylesterase activities, were measured spectrophotometrically. The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower (for all, p < 0.001), whereas the serum MDA levels were significantly higher in the patients with SSRI intoxication than in the controls (p < 0.001). These results indicated that decreased PON1 activity and increased oxidative stress represent alternative mechanisms in SSRI toxicity. More studies are needed to elucidate the role of PON1 activity in the etiology of SSRI intoxication.     

Inherited and acquired interactions between ACHE and PON1 polymorphisms modulate plasma acetylcholinesterase and paraoxonase activities

The 5.5 Mb chromosome 7q21-22 ACHE/PON1 locus harbours the ACHE gene encoding the acetylcholine hydrolyzing, organophosphate (OP)-inhibitable acetylcholinesterase protein and the paraoxonase gene PON1, yielding the OP-hydrolyzing PON1 enzyme which also displays arylesterase activity. In search of inherited and acquired ACHE-PON1 interactions we genotyped seven polymorphic sites and determined the hydrolytic activities of the corresponding plasma enzymes and of the AChE-homologous butyrylcholinesetrase (BChE) in 157 healthy Israelis. AChE, arylesterase, BChE and paraoxonase activities in plasma displayed 5.4-, 6.5-, 7.2- and 15.5-fold variability, respectively, with genotype-specific differences between carriers of distinct compound polymorphisms. AChE, BChE and arylesterase but not paraoxonase activity increased with age, depending on leucine at PON1 position 55. In contrast, carriers of PON1 M55 displayed decreased arylesterase activity independent of the - 108 promoter polymorphism. Predicted structural consequences of the PON1 L55M substitution demonstrated spatial shifts in adjacent residues. Molecular modelling showed substrate interactions with the enzyme variants, explaining the changes in substrate specificity induced by the Q192R substitution. Intriguingly, PON1, but not BChE or arylesterase, activities displayed inverse association with AChE activity. Our findings demonstrate that polymorphism(s) in the adjacent PON1 and ACHE genes affect each other's expression, predicting for carriers of biochemically debilitating ACHE/PON1 polymorphisms adverse genome-environment interactions.     

Assessment of paraoxonase activities in patients with knee osteoarthritis

The objective of this study was to investigate serum paraoxonase and arylesterase activities, and lipid hydroperoxide (LOOH) and total thiol (total free sulfhydryl groups, -SH) levels along with lipid parameters in patients with knee osteoarthritis. Thirty-six patients with knee osteoarthritis and 30 healthy individuals were enrolled in the study. Serum paraoxonase and arylesterase activities were measured spectrophotometrically. LOOH levels were measured by ferrous oxidation with xylenol orange assay (FOX-2). Serum high-density lipoprotein-cholesterol (HDL-C), -SH levels, paraoxonase and arylesterase activities were significantly lower in the patient group than those in the controls (P < 0.05, for all), while LOOH and low-density lipoprotein (LDL) levels were significantly higher. In conclusion, paraoxonase and arylesterase activities were decreased significantly in patients with knee osteoarthritis. Lower serum paraoxonase-1 activity and lower level of HDL-C seem to be related to increased oxidative stress and inflammatory condition in these patients. It is known that paraoxonases reduce oxidative stress in serum and tissues thereby protecting against cardiovascular disease, particularly atherosclerosis. Thus, decreased paraoxonase and arylesterase activities play a role in the pathogenesis of atherosclerosis through increased susceptibility to lipid peroxidation in patients with osteoarthritis.     

Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH

Purified serum paraoxonase (PON1) had been shown to attenuate the oxidation of LDL in vitro. We critically reevaluated the antioxidant properties of serum PON1 in the in vitro assays initiated with copper or the free radical generator 2,2'-azobis-2-amidinopropane hydrochloride (AAPH). The antioxidant activity of different purified PON1 preparations did not correlate with their arylesterase (AE), lactonase, or phospholipase A2 activities or with the amounts of detergent or protein. Dialysis of three of these preparations resulted in a 30-40% loss of their AE activities but in a complete loss of their antioxidant activities. We also followed the distribution of the antioxidant activity during human serum PON1 purification by two purification methods. The antioxidant activity of the anion-exchange chromatography fractions did not copurify with PON1 using either method and could largely be accounted for by the "antioxidant" activity of the detergent present. In conclusion, using the copper or AAPH in vitro assays, no PON1-mediated antioxidant activity was detected, suggesting that the removal of PON1 from its natural environment may impair its antioxidative activity and that this assay with highly purified PON1 may be an inappropriate method with which to study the antioxidative properties of the enzyme.     

Comparative modeling of PON2 and analysis of its substrate binding interactions using computational methods

Paraoxonase (PON) constitutes a family of calcium-dependent mammalian enzymes comprising of PON1, PON2, and PON3. PON family shares ~60% sequence homology. These enzymes exhibit multiple activities like paraoxonase, arylesterase, and lactonase in a substrate dependent manner. Decreased PON activity has been reported in diseases like cardiovascular disease, atherosclerosis, and diabetes. Even though, PON2 is the oldest member of the family, PON1 is the only member studied in silico. In this study, the structure of PON2 was modeled using MODELLER 9v7 and its interactions with relevant ligands and it's physiological substrate homocysteine thiolactone was performed using AutoDock 4.0. The results reveal that PON1 and PON2 share common ligand binding patterns for arylesterase and lactonase activity, whereas in case of paraoxon binding, the residues involved in the interactions were different. Interestingly, the substrate HCTL was found to have the lowest free energy of binding (ΔG) and highest affinity for PON2 than PON1.     

High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism

Autism is a behaviorally defined disorder of unknown etiology that is thought to be influenced by genetic and environmental factors. High levels of homocysteine and oxidative stress are generally associated with neuropsychiatric disorders. The purpose of this study was to compare the level of homocysteine and other biomarkers in children with autism to corresponding values in age-matched healthy children. We measured total homocysteine (tHcy), vitamin B(12), paraoxonase and arylesterase activities of human paraoxonase 1 (PON1) in plasma and glutathione peroxidase (GPx) activity in erythrocytes from 21 children: 12 with autism (age: 8.29 +/- 2.76 years) and 9 controls (age: 8.33 +/- 1.82 years). We found statistically significant differences in tHcy levels and in arylesterase activity of PON1 in children with autism compared to the control group: 9.83 +/- 2.75 vs. 7.51 +/- 0.93 micromol/L (P < or =0.01) and 72.57 +/- 11.73 vs. 81.83 +/- 7.39 kU/L (P < or =0.005). In the autistic group there was a strong negative correlation between tHcy and GPx activity and the vitamin B(12) level was low or suboptimal. In conclusion, our study shows that in children with autism there are higher levels of tHcy, which is negatively correlated with GPx activity, low PON1 arylesterase activity and suboptimal levels of vitamin B(12).     

Paraoxonase 1 activities and polymorphisms in autism spectrum disorders

Autism spectrum disorders (ASD) comprise a complex and heterogeneous group of conditions of unknown aetiology, characterized by significant disturbances in social, communicative and behavioural functioning. Recent studies suggested a possible implication of the high-density lipoprotein associated esterase/lactonase paraoxonase 1 (PON1) in ASD. In the present study, we aimed at investigating the PON1 status in a group of 50 children with ASD as compared to healthy age and sex matched control participants. We evaluated PON1 bioavailability (i.e. arylesterase activity) and catalytic activity (i.e. paraoxonase activity) in plasma using spectrophotometric methods and the two common polymorphisms in the PON1 coding region (Q192R, L55M) by employing Light Cycler real-time PCR. We found that both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with less active variants of the PON1 gene was found. The PON1 phenotype, inferred from the two-dimensional enzyme analysis, had a similar distribution in the ASD group and the control group. In conclusion, both the bioavailability and the catalytic activity of PON1 are impaired in ASD, despite no association with the Q192R and L55M polymorphisms in the PON1 gene and a normal distribution of the PON1 phenotype.     

The age-related paraoxonase 1 response is altered by long-term caloric restriction in male and female rats

Caloric restriction (CR) has been shown to attenuate age-related oxidative damage and to improve major atherosclerotic risk factors. Paraoxonase 1 (PON1), an enzyme specifically associated with HDL containing apolipoproteins A-I and J, has been reported to prevent the proatherosclerotic effects of oxidized LDL. The aim of this study was to evaluate whether modulation of PON1 activity is part of the underlying CR mechanisms that attenuate the age-associated negative effects. Experimental groups were 1 year old rats of both genders subjected to 40% CR for 1 year and two ad libitum-fed groups, also including rats of both genders, euthanized at 6 months or 2 years. Aging impaired the serum lipid profile and increased lipid peroxidation, PON1 activities, and the content of both PON1 and apolipoprotein J in HDL, which suggests an HDL subfraction redistribution to protect LDL more effectively from oxidation. The CR-associated improved lipid profile and the decreased lipid peroxide levels would lead to the decreased arylesterase activity seen in old CR animals, suggesting that PON1 modulation is not an integral part of the main antioxidant mechanisms of CR but rather that CR would determine a more youthful and less oxidative situation in which the protection of LDL would be less necessary.     

Antioxidant Status in Blood of Obese Children: The Relation between Trace Elements,Paraoxonase, and Arylesterase Values

Obesity is known to lead to complications involving several systems. The basic mechanism in obesity-related complications is chronic inflammation and increased oxidative stress. Trace element levels in obese children may vary due to poor nutritional habits. The purpose of this study was to investigate the relation between serum paraoxonase (PON1) and arylesterase (ARE) levels, markers of the oxidant–antioxidant balance in the body, and serum zinc (Zn), copper (Cu), manganese (Mn), and selenium (Se) concentrations in obese children. Fifty-seven overweight patients aged 6–17 and 48 age- and sex-matched healthy children were included in the study. Serum PON1 and ARE activity levels were measured, together with Cu, Zn, Mn, Se, total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, glucose, aspartate amino transferase, and alanine amino transferase levels. PON1 and ARE activity levels were significantly lower in obese patients compared to those in healthy individuals (P?<?0.05). Various changes were determined in Cu, Zn, Mn, and Se levels between the study and control groups (P?<?0.05). In terms of the relation between trace elements and PON1 and ARE levels, a significant positive correlation was determined between serum Se and PON1 levels in the study group (P?<?0.05, r?=?0.31). No significant correlation was determined between other trace element levels and PON1 and ARE levels (P?>?0.05). In conclusion, the detection in our study of a positive correlation between Se and PON1 levels in obese children may be significant in terms of showing a relation between Se and antioxidant systems in obese children.     

The paraoxonase gene family and coronary heart disease

PURPOSE OF REVIEW: The antioxidant activity of high-density lipoprotein is largely due to the paraoxonase 1 located on it. Experiments with transgenic paraoxonase 1 knock-out mice indicate the potential for this enzyme to protect against atherogenesis. This effect of high-density lipoprotein in decreasing low-density lipoprotein lipid peroxidation is maintained for longer than that of antioxidant vitamins and could thus be more protective. Several important advances in the field of paraoxonase research have occurred during this review period, not least the discovery that two other members of the paraoxonase gene family, PON2 and PON3, may also have important antioxidant properties. Significant advances have been made in understanding the basic biochemical function of paraoxonase 1 and the discovery of possible modulators of its activity. RECENT FINDINGS: Decreased coronary heart disease risk associated with polymorphisms of paraoxonase 1, which are most active in lipid peroxide hydrolysis, as revealed by meta-analysis is likely to be an underestimate of the true contribution of paraoxonase 1 to coronary heart disease because these polymorphisms explain only a small component of the variation in paraoxonase 1 activity. It is a very important observation, however, because genetic influences are not likely to be confounded by other factors linked with both coronary heart disease and diminished paraoxonase 1 activity. SUMMARY: Although advances have been made in research into the paraoxonase family and atherosclerosis, much more needs to be done. Paraoxonase 1 is much the most extensively researched and strategies will hopefully emerge to increase its activity and provide a more satisfactory test of the antioxidant hypothesis of atherosclerosis than antioxidant vitamins have done.     

Effect of statin therapy on paraoxonase-1 status: A systematic review and meta-analysis of 25 clinical trials

BackgroundDecreased 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.ObjectiveTo systematically 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.MethodsScopus and Medline databases were searched to identify clinical trials. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the one-study remove approach. Random-effects meta-regression was performed to assess the impact of potential confounders on the estimated effect sizes.ResultsMeta-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.ConclusionThe 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.