Lower Paraoxonase Activity Research Articles

Quantitative Assessment of the Influence of Paraoxonase 1 Activity and Coronary Heart Disease Risk

Human paraoxonase 1 (PON1) is a calcium-dependent high-density lipoprotein associated ester hydrolase that has attracted considerable attention as a candidate factor for coronary heart disease (CHD) based on its function as a key factor in lipoprotein catabolism pathways. This meta-analysis aimed to clarify the inconsistency of published studies and to establish a comprehensive picture of the relationship between PON1 activity and CHD susceptibility. A systematic search was performed from PubMed, Web of Science, EMBASE, and CNKI databases. Ratio of means (RoM) between case and control and 95% confidence intervals (CIs) were calculated using a random-effects model. The source of heterogeneity was explored by subgroup analysis and meta-regression. We identified 47 eligible studies including a total of 9853 CHD cases and 11,408 controls. The pooled analysis showed that CHD patients had a 19% lower PON1 activity than did the controls (RoM=0.81; 95% CI: 0.74-0.89, p<10(-5)). In the subgroup analyses by CHD end points, a similar effect size was observed with coronary stenosis and myocardial infarction subgroups, with corresponding RoM of 0.81 (95% CI: 0.73-0.89, p<10(-4)) and 0.83 (95% CI: 0.74-0.93, p=0.001), respectively. Decreased PON1 activity associated with CHD risk was observed in almost all subgroup analysis according to ethnicity, sample size, study design, mean age of cases, source, and type of control. Decreased PON1 activity may act as a risk factor for the development of CHD. Progressive decrease in serum PON1 activity may exist for an individual with severe disease. However, larger studies using a prospective approach are needed to confirm our results.

Altered inflammation, paraoxonase-1 activity and HDL physicochemical properties in obese humans with and without Prader-Willi syndrome.

SUMMARYPrader-Willi syndrome (PWS) represents the most common form of genetic obesity. Several studies confirm that obesity is associated with inflammation, oxidative stress and impairment of antioxidant systems; however, no data are available concerning PWS subjects. We compared levels of plasma lipids and C-reactive protein (CRP) in 30 subjects of ‘normal’ weight (18.5–25 kg/m2), 15 PWS obese (>30 kg/m2) subjects and 13 body mass index (BMI)-matched obese subjects not affected by PWS. In all subjects, we evaluated the levels of lipid hydroperoxides and the activity of paraoxonase-1 (PON1), an enzyme involved in the antioxidant and anti-inflammatory properties exerted by high-density lipoproteins (HDLs). Furthermore, using the fluorescent molecule of Laurdan, we investigated the physicochemical properties of HDLs isolated from normal weight and obese individuals. Altogether, our results demonstrated, for the first time, higher levels of lipid hydroperoxides and a lower PON1 activity in plasma of obese individuals with PWS with respect to normal-weight controls. These alterations are related to CRP levels, with a lower PON1:CRP ratio in PWS compared with non-PWS obese subjects. The study of Laurdan fluorescence parameters showed significant modifications of physicochemical properties in HDLs from PWS individuals. Whatever the cause of obesity, the increase of adiposity is associated with inflammation, oxidative stress and alterations in HDL compositional and functional properties.

Regulation of Hepatic Paraoxonase-1 Expression

Serum paraoxonase-1 (PON1) is a member of the paraoxonases family (PON1, PON2, and PON3). PON1 is synthesized and secreted by the liver, and in circulation it is associated with HDL. PON1 has antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions and to attenuate atherosclerosis development. Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease and is an independent risk factor for coronary artery disease. Therefore, pharmacological modulation of PON1 activity or PON1 gene expression could constitute a useful approach for preventing atherosclerosis. A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. Together with the enzyme secretion rate, enzymatic turnover, and protein stability, the level of PON1 gene expression is a major determinant of PON1 status. This paper summarizes recent progress in understanding the regulation of PON1 expression in hepatocytes.

Lipid Peroxidation and Paraoxonase-1 Activity in Celiac Disease

Paraoxonase-1 (PON1) plays an antioxidant and anti-inflammatory role. Aim of the study was to investigate the alteration of paraoxonase-1 activity in celiac disease (CD), an intestinal disorder characterized by toxic injury exerted by gluten peptides. Activities of PON1, levels of biochemical markers of lipid peroxidation and total antioxidant capacity were evaluated in serum obtained from 27 celiac patients (11 at diagnosis, 16 treated with gluten free diet) and 25 healthy subjects. Moreover, the serum susceptibility of Cu2+-induced lipid peroxidation was investigated in controls and patients. The results showed a lower PON1 activity in serum of both groups of celiac patients with respect to control subjects. PON1 activity in CD was related with markers of disease severity and was negatively correlated with the levels of lipid hydroperoxide and with the susceptibility of serum to lipid peroxidation induced in vitro by metal ions. The alteration of PON1 activity and markers of lipid peroxidation realized at lower extent in patients who were on a gluten-free diet.

Effect of cigarette smoking on paraoxonase 1 activity according to PON1 L55M and PON1 Q192R gene polymorphisms

This study aims to investigate the effect of cigarette smoking on paraoxonase1 (PON1) activity according to PON1 L55M and PON1 Q192R gene polymorphisms. Our sample included 300 voluntary subjects: 138 nonsmokers and 162 current smokers aged 38.47±21.91 and 35.55±16.03years, respectively. PON1 activity was determined by kinetic methods. L55M and Q192R gene polymorphisms of PON1 were determined by multiplex polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). We found in smokers a significant decrease of PON1 activity before and after adjustment. We noted a significant association between smoking status and lower PON1 activity [odds ratio (OR)=3.03, confidence interval 95%=1.5-5.9, p=0.001]. In smokers, there was significant association between PON1 activity and PON1 L55M polymorphisms (p=0.01). Also, the 55MM genotype presented the lowest paraoxonase activity, while the 55LL genotype showed the highest one. After adjustment for confounding variables, smokers with PON1 L55M polymorphism had the highest risk for lower PON1 activity; however, PON1 Q192R genotype might protect smokers from decrease in PON1 activity. We found significant interaction between the effect of cigarette smoking and both PON1 L55M and PON1 Q192R polymorphisms on lower PON1 activity. Cigarette smoking was significantly associated with decrease in PON1 activity. Moreover, PON1 L55M polymorphism predisposes smokers to decreased PON1 activity in contrast to PON1 Q192R genotype.

Correlation between lipoprotein(a) and lipid peroxidation in psoriasis: role of the enzyme paraoxonase-1

Psoriasis is a chronic, inflammatory skin disease associated with abnormal plasma lipid metabolism and with a high frequency of cardiovascular events. Modifications of plasma lipids and an increase in the levels of biochemical markers of lipid peroxidation have been reported in subjects with psoriasis, suggesting a relationship between psoriasis, lipoproteins and oxidative damage. To investigate further the relationship between lipoproteins and oxidative stress in psoriasis. The levels of plasma lipids, lipoprotein(a) [Lp(a)] and markers of lipid peroxidation were evaluated in subjects with psoriasis (n=23) and in controls (n=25). In the same subjects, the activity of paraoxonase-1 (PON1), an antioxidant and an anti-inflammatory enzyme associated with high-density lipoproteins, was investigated. The results showed higher levels of Lp(a) in the serum of patients with psoriasis compared with controls (P<0·001). Higher levels of lipid hydroperoxides (P<0·001) and lower PON1 activity were observed in the serum of patients compared with healthy subjects, confirming that psoriasis is associated with oxidative stress. The imbalance between oxidative stress and antioxidant enzymes, and the increase of Lp(a) serum levels was related to the extent and severity of psoriasis. Finally, our results demonstrated that Lp(a) levels were positively correlated with markers of lipid peroxidation and negatively related to PON1 activity, suggesting that subjects with higher levels of Lp(a) are more exposed to oxidative damage. Our results provide further evidence that oxidative stress and impairment of the antioxidant system in the plasma of patients may play a role in pathogenesis and progression of psoriasis and related complications.

Evaluation of paraoxonase 1 arylesterase activity and lipid peroxide levels in patients with type 1 diabetes

Poor metabolic control of type 1 diabetes is one of the most important factors accelerating the development of late diabetic complications. Several other factors that might contribute to this process are currently being investigated. Low paraoxonase 1 (PON1) activity and high lipid peroxide (LPO) levels contribute to endothelial damage, but it remains unclear whether they are critical for the development of late diabetic complications. The aim of the study was to evaluate PON1 arylesterase activity and LPO levels in patients with type 1 diabetes and to investigate whether these parameters are associated with metabolic control and late complications. Moreover, we aimed to establish whether PON1 activity and LPO levels differ between women and men with type 1 diabetes. The study involved 80 patients with type 1 diabetes and 24 healthy subjects. PON1 activity was measured by a spectrophotometric method. LPO levels were measured by a commercial assay kit. Diabetic patients had lower PON1 activity and higher LPO levels than healthy people. We observed a negative correlation between PON1 activity and LPO levels in diabetic patients. There was no association between PON1 activity or LPO levels and metabolic parameters or late diabetic complications. There was a positive correlation between LPO levels and the body mass index (BMI) in women with type 1 diabetes. Our study showed that low PON1 activity and high LPO levels are not the most critical factors involved in late diabetic complications in type 1 diabetes. Increased LPO levels in women with type 1 diabetes may result from enhanced lipogenesis in this subgroup compared with diabetic men.

Unraveling the Pharmacogenetics of Clopidogrel

Clopidogrel forms a cornerstone in the treatment of patients undergoing coronary stenting. Although the clinical effectiveness of clopidogrel has been shown repeatedly in large clinical trials, there appears to be a large interindividual response variability that influences the risk of atherothrombotic events.1,2 Studies3,4 have shown that differences in the plasma concentration of the active metabolite of clopidogrel are an important determinant of its antiplatelet effect. Although several environmental factors influence the formation of the active metabolite, most variation appears to be genetic.5 Numerous studies5–7 have shown that polymorphisms in genes encoding the cytochrome (CYP) p450 system, especially CYP2C19, influence bioactivation of clopidogrel and, hence, the risk of cardiovascular events, especially stent thrombosis. Still, polymorphic variation in CYP2C19 seems to explain only 5% to 11% of the response variability to clopidogrel, leaving variation in bioactivation of clopidogrel largely unexplained.5,8 Article see p 422 A new player in the pharmacogenetics of clopidogrel was introduced by Bouman et al,9 who identified paraoxonase-1 (PON1) as a major determinant of the bioactivation and clinical efficacy of clopidogrel in a series of elegant experiments and clinical studies among subjects from European descent. This hepatic esterase is associated with high-density lipoprotein and has antioxidative effects on low-density lipoprotein and macrophages. Bouman et al identified PON1 as the crucial enzyme for the bioactivation of clopidogrel, with its common Q192R polymorphism determining the rate of active thiol metabolite formation. In a case-cohort study among 41 cases with stent thrombosis and 71 control subjects, the Q allele was dose-dependently associated with lower PON1 activity and active metabolite concentrations in plasma, reduced platelet inhibition, and a higher risk of stent thrombosis. Q192R explained >70% of the response variability to clopidogrel. The authors corroborated their findings in a …

Pulmonary function, oxidative stress and inflammatory markers in severe COPD exacerbation

Oxidative stress and inflammation play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Pulmonary function, oxidative stress parameters and inflammatory markers were measured in 74 patients with severe COPD exacerbation and 41 healthy subjects. In patients all parameters were assessed at two time points: Firstly, one day after admission and secondly, after 7 10 days when they were clinically stable enough to be discharged. Patients were divided in two groups according the presence of ischemic heart disease (IHD): IHD positive (IHD+) patients and IHD negative (IHD-) patients. During hospitalisation O2•-, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and total oxidant status (TOS) increased and were higher at discharge compared with admission and the control group. Superoxide dismutase (SOD) activity was significantly lower in COPD patients at both time points compared with the control group. Total antioxidant status (TAS) was significantly lower and the prooxidant-antioxidant balance (PAB) was higher at both time points in COPD patients compared with the control group. High sensitive C-reactive protein (hsCRP) and also the neutrophil count were significantly higher at admission compared with discharge. Paraoxonase 1 (PON1) enzymatic activities in COPD patients did not differ compared with the control group. IHD+ COPD patients had significantly lower PON1 activity but higher PAB levels and hsCRP concentrations, compared with IHD COPD patients. The oxidant/antioxidant imbalance was significantly pronounced in patients with COPD exacerbation for at least 24 hours following their admission and when they were clinically stable enough to be discharged. Increased oxidative stress, elevated systemic inflammation and decreased antioxidant defence were common in end-stage disease and particularly COPD patients with ischemic heart disease.

Increased LCAT activity and hyperglycaemia decrease the antioxidative functionality of HDL

Type 2 diabetes mellitus increases the risk of atherosclerotic cardiovascular disease. Antioxidative properties of high density lipoprotein (HDL) are important for atheroprotection. This study investigated whether the antioxidative functionality of HDL is altered in type 2 diabetes mellitus and aimed to identify potential determinants of this parameter. In a cross-sectional study, we investigated 74 patients with type 2 diabetes and 75 control subjects. Antioxidative properties of HDL were measured and expressed as either (i) HDL antioxidative capacity or (ii) HDL antioxidation index after multiplying HDL antioxidative capacity results with individual plasma HDL cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) and paraoxonase-1 (PON-1) activities were determined. HDL antioxidative capacity was similar in patients with diabetes and controls, while the HDL antioxidation index was decreased in patients with diabetes (P = 0.005) owing to lower plasma HDL cholesterol (P < 0.001). LCAT activity was higher and PON-1 activity lower in type 2 diabetes mellitus (each P < 0.001). In the combined subjects, HDL antioxidative capacity was inversely related to LCAT activity (P < 0.01). The HDL antioxidation index correlated negatively with blood glucose (P < 0.001), HbA1c and LCAT activity (each P < 0.01), and positively with PON-1 activity (P < 0.01). Multiple linear regression analysis demonstrated that high LCAT activity was associated with both decreased HDL antioxidation capacity (P < 0.05) and index (P < 0.001) independent of diabetes status, glycaemic control and PON-1. Overall, the antioxidative functionality of HDL is impaired in type 2 diabetes mellitus mostly because of lower HDL cholesterol. Hyperglycaemia, increased LCAT activity and lower PON-1 activity likely contribute to impaired antioxidative functionality of HDL.

Serum paraoxonase activity and oxidative stress in patients with adult nephrotic syndrome

ObjectiveIt has been shown that low paraoxonase-1 (PON1) activity is associated with a risk of an early development of atherosclerosis. In the present study, we investigated serum paraoxonase, and arylesterase activities and oxidative stress in patients with adult nephrotic syndrome (NS). In addition, we examined the relationship between these measurements and atherosclerosis. MethodsTwenty-one patients with NS and 21 healthy controls were enrolled in the study. Serum basal and salt-stimulated paraoxonase activities, arylesterase activity, lipid hydroperoxide (LOOH) and total thiol (SH) levels were measured. ResultsSerum basal and salt-stimulated paraoxonase activities, arylesterase activity and total SH levels were significantly lower in patients with NS than in controls (p<0.05, p<0.05, p<0.01 and p<0.05, respectively), whereas LOOH levels were significantly higher (p<0.05). Serum LOOH levels were significantly correlated with total-SH levels in patients with NS (r=−0.467; p<0.01). Moreover, proteinuria levels were significantly correlated with serum LOOH levels (r=0.397; p<0.01), whereas no correlation was found among serum paraoxonase activity, arylesterase activity and total-SH levels in NS patients (p>0.05). ConclusionsWe concluded that oxidative stress is increased, while serum PON1 activity is decreased in patients with adult NS. In addition, these results indicate that lower PON1 activity is associated with an oxidant–antioxidant imbalance that may contribute to atherosclerosis in adult patients with NS.

Lower Serum Paraoxonase-1 Activity Is Related to Higher Serum Amyloid A Levels in Metabolic Syndrome

High-density lipoproteins (HDL) contain the anti-oxidative enzyme, paraoxonase-1 (PON-1), which is important for atheroprotection. The acute phase reactant, serum amyloid A (SAA), an HDL-associated apolipoprotein, may impair PON-1 activity, whereas SAA and PON-1 are reciprocally regulated in response to acute inflammatory stimuli. The relationship of serum PON-1 activity with SAA during low-grade chronic inflammation is unclear. Here we tested the extent to which low serum PON-1 activity is related to high SAA levels in subjects with and without metabolic syndrome (MetS). In 19 nondiabetic subjects with MetS and 67 subjects without MetS, serum PON-1, assayed as its arylesterase activity, and SAA were measured together with plasma lipids and lipoproteins, high-sensitive C-reactive protein (hs-CRP) and insulin resistance (homeostasis model assessment (HOMA(ir)). PON-1 activity was decreased (p=0.023), whereas SAA levels were increased (p=0.042) in MetS subjects, coinciding with higher hs-CRP levels and HOMA(ir) values. Multiple linear regression analysis revealed that age- and gender-adjusted PON-1 activity was related inversely to SAA (β=-0.256, p=0.020) after adjustment for MetS, or alternatively for hs-CRP and HOMA(ir) (β=-0.271, p=0.049). Decreased serum PON-1 activity in MetS may in part be attributable to higher SAA levels. We suggest that higher SAA levels contribute to impaired HDL anti-oxidative function in MetS via an effect on PON-1 regulation.

Effect of Exercise Training on Plasma Levels and Functional Properties of High-Density Lipoprotein Cholesterol in the Metabolic Syndrome

Intense lifestyle modifications can change the high-density lipoprotein (HDL) cholesterol concentration. The aim of the present study was to analyze the early effects of short-term exercise training, without any specific diet, on the HDL cholesterol plasma levels and HDL functional characteristics in patients with the metabolic syndrome (MS). We studied 30 sedentary subjects, 20 with and 10 without the MS. The patients with the MS underwent moderate intensity exercise training for 3 months on bicycle ergometers. Blood was sampled before and after training for biochemical analysis, paraoxonase-1 activity, and HDL subfraction composition and antioxidative capacity. Lipid transfer to HDL was assayed in vitro using a labeled nanoemulsion as the lipid donor. At baseline, the MS group had greater triglyceride levels and a lower HDL cholesterol concentration and lower paraoxonase-1 activity than did the controls. Training decreased the plasma triglycerides but did not change the low-density lipoprotein or HDL cholesterol levels. Nonetheless, exercise training increased the HDL subfractions' antioxidative capacity and paraoxonase-1 activity. After training, the MS group had compositional changes in the smallest HDL subfractions associated with increased free cholesterol and cholesterol ester transfers to HDL, reaching normal values. In conclusion, the present investigation has added relevant information about the dissociation between the quantitative and qualitative aspects of HDL after short-term exercise training without any specific diet in those with the MS, highlighting the importance of evaluating the functional aspects of the lipoproteins, in addition to their plasma levels.

Directed Evolution of a Thermostable Quorum-quenching Lactonase from the Amidohydrolase Superfamily

A thermostable quorum-quenching lactonase from Geobacillus kaustophilus HTA426 (GI: 56420041) was used as an initial template for in vitro directed evolution experiments. This enzyme belongs to the phosphotriesterase-like lactonase (PLL) group of enzymes within the amidohydrolase superfamily that hydrolyze N-acylhomoserine lactones (AHLs) that are involved in virulence pathways of quorum-sensing pathogenic bacteria. Here we have determined the N-butyryl-L-homoserine lactone-liganded structure of the catalytically inactive D266N mutant of this enzyme to a resolution of 1.6 Å. Using a tunable, bioluminescence-based quorum-quenching molecular circuit, the catalytic efficiency was enhanced, and the AHL substrate range increased through two point mutations on the loops at the C-terminal ends of the third and seventh β-strands. This E101N/R230I mutant had an increased value of k(cat)/K(m) of 72-fold toward 3-oxo-N-dodecanoyl-L-homoserine lactone. The evolved mutant also exhibited lactonase activity toward N-butyryl-L-homoserine lactone, an AHL that was previously not hydrolyzed by the wild-type enzyme. Both the purified wild-type and mutant enzymes contain a mixture of zinc and iron and are colored purple and brown, respectively, at high concentrations. The origin of this coloration is suggested to be because of a charge transfer complex involving the β-cation and Tyr-99 within the enzyme active site. Modulation of the charge transfer complex alters the lactonase activity of the mutant enzymes and is reflected in enzyme coloration changes. We attribute the observed enhancement in catalytic reactivity of the evolved enzyme to favorable modulations of the active site architecture toward productive geometries required for chemical catalysis.

Effect of non-genetic factors on paraoxonase 1 activity in patients undergoing hemodialysis

Objectives Hemodialyzed patients have lower paraoxonase 1 (PON1) activity. Higher mortality risk from cardiovascular disease observed in these patients could be due to the low antiathetrogenic activity of PON1. Understanding the mechanism that causes lower PON1 activity could provide the possibility for modulation of enzyme activity in purpose of preventing and/or decreasing development of atherosclerosis. Design and methods 87 healthy individuals and 71 hemodialyzed patients were enrolled in this study. Results Hemodialyzed patients had reduced PON1 paraoxonase and arylesterase activity, concentrations of HDL, HDL 3 and HDL 2 and concentrations of free thiol groups. Distribution of HDL subfractions and distribution of PON1 phenotypes as well as concentrations of MDA were not different between two study groups. In the in vitro experiment high concentrations of urea, creatinine, uric acid and addition of patient's sera ultrafiltrate did not significantly affect PON1 paraoxonase activity. Conclusion Decreased HDL concentration as well as lower PON1 concentration (shown indirectly by the enzyme arylesterase activity) might contribute, at least partly, to the reduced PON1 activity observed in hemodialyzed patients. Decreased concentration of free thiol groups in sera suggest that free thiol group (Cys284) in PON1 might also be oxidized, which can affect PON1 activity.

Lipid status, paraoxonase-1 activity and metabolic parameters in serum of heifers and lactating cows related to oxidative stress

The objective of this study was to investigate serum lipids, metabolic parameters and activity of the anti-oxidative enzyme paraoxonase-1 (PON1). The study was conducted on non-pregnant heifers with optimal health status and on healthy dairy cows in the period of intensive lactation, assuming that the energy and metabolic demands during lactation reduce anti-oxidative protection. Total cholesterol and HDL-cholesterol concentrations were significantly higher ( P < 0.05) in lactating cows than in heifers. Bilirubin concentration and γ-glutamyltransferase (GGT) activity were also significantly higher in lactating cows ( P < 0.05), indicating increased hepatic efforts of cows to meet energy requirements for lactation. Significantly lower PON1 activity and PON1/HDL ratio in lactating cows compared to heifers ( P < 0.05) showed that metabolic efforts during pregnancy, parturition and lactation influence PON1 activity due to oxidative stress. Concurrent increase in total and HDL-cholesterol during lactation indicated that the HDL particle is a major carrier of cholesterol in cows.

Decreased human paraoxonase-1 activity in patients with Sjogren's syndrome

The aim of the study was to examine human serum paraoxonase 1 (PON1) activity, phenotype distribution and lipid parameters in patients with Sjögren's syndrome. The prevalence of cardio- and cerebrovascular diseases in SS patients was also evaluated after a 5-year follow-up. Fifty-seven SS patients and 17 age-matched healthy controls were enrolled into the study. PON1 and arylesterase activities were measured spectrophotometrically. The phenotype distribution of PON1 was determined by the dual-substrate method. Significantly lower PON1 activity was found in patients with SS compared with the control group (98.00 +/- 69.21 versus 203.3 +/- 92.78 U ml(-1); P < 0.001). There were significant differences in PON1 phenotype distribution of SS patients and controls (AA/AB/BB: 91.2/8.8/0 versus 58.8/29.4/11.8%; P < 0.01). No significant correlations were found between PON activity and disease-characteristic autoantibodies, including anti-Ro/SS-A and anti-La/SS-B concentrations. PON activity did not predict the cerebro/cardiovascular risk in SS patients during the 5-year follow-up. Despite the relatively small sample size that reduces the power of the study, decreased PON activity may be a possible cardiovascular risk factor in SS. Disadvantageous PON1 phenotype distribution may contribute to the decreased PON activity in these patients.

Interaction Between Organophosphate Exposure and Serum PON1 Activity on Hypophysary and Male Sexual Hormones in Mexican Greenhouse Workers

ISEE-0483 Background and Objective: Previous studies have found that organophosphate (OP) may act as endocrine disruptors. Paraoxonase1 (PON1) hydrolyzes the active metabolites of OP insecticides. People with a low PON1 activity have demonstrated an increased susceptibility to OP. The objective of this study was to evaluate the effect of interaction between OP exposure and serum PON1 activity on male hormone profile. Methods: A longitudinal study was conducted from July 2004–May 2005. A total of 137 men (18–52 years old) agreed to participate during the rainy season and 85 of them accepted again during the dry season. A general questionnaire, urine and blood samples were taken a day after pesticide application. Urine dialkylphosphates (DAP) were analyzed by gas chromatography. Serum samples were analyzed for FSH, LH, testosterone, estradiol, inhibin B and prolactin by immunoassay. Serum PON1 activity towards phenylacetate, paraoxon and diazoxon were determined as described by Richter and Furlong 1999, and serum p,p‘-DDE levels by gas chromatography. Molar quantities (mmol/L) of dimethyl DAP and diethyl DAP were calculated. The interaction effect between DAP levels and serum PON1 activity on serum hormones levels was evaluated using Generalized Estimated Equation models adjusted by potential confounders including serum p,p’-DDE. Results: A significant interaction (P = 0.05) was found between diazoxonase activity and SDAP on inhibin B levels. We observed a decrease in the percentage of variation of inhibin B for each increment in one unit of the logarithm concentration of åDAP together with diazoxonase activity increase (last quintile:-14.7 vs first quintile:-6.4%). The effect of interaction between dimethyl DAP and paraoxonase activity on testosterone was near to statistical significance (P = 0.06). No significant interaction was observed between serum PON1 activity an DAP levels on the other hormones. Conclusion: We found an effect of interaction between OP exposure and PON1 activity on serum inhibin B and testoterone levels.

Variation in paraoxonase-1 activity and atherosclerosis

Paraoxonase-1 (PON1) is an HDL-associated protein of 354 amino acids with a molecular mass of 43 000 Da. It is synthesized in the liver, and in serum it is almost exclusively associated with HDL. PON1 has been reported to be an important contributor to the antioxidant and anti-inflammatory activities of HDL. PON1 impedes oxidative modification of LDL. PON1 serum activity is related to systemic lipid peroxidation stress and prospective cardiovascular risk. In this review, we discuss the relationship between PON1 activity and atherosclerotic diseases and various factors modulating PON1 activity including genes, age, lifestyle factors and medical conditions. Finally, evidence that pharmacological agents may affect PON1 activity is summarized. There is increasing evidence from both animal and human studies linking low PON1 activity to an increased likelihood of cardiovascular diseases. Two prospective studies reported a significantly lower incidence of major cardiovascular events in participants with the highest systemic PON1 activity, compared with those with the lowest activity. PON1 is a potentially antiatherogenic HDL-associated enzyme that protects LDL from oxidative modification. Enhancing PON1 activity could be an important target for future pharmacological agents aimed at decreasing cardiovascular risk.

Serum cholinesterase inhibition in relation to paraoxonase-1 (PON1) status among organophosphate-exposed agricultural pesticide handlers.

BackgroundAnimal studies have demonstrated that low paraoxonase-1 (PON1) status (i.e., low catalytic efficiency and/or low plasma PON1 activity) is associated with neurotoxic effects after exposure to several organophosphate (OP) insecticides. However, few human studies have investigated associations between PON1 status and intermediate end points, such as serum cholinesterase [butyrylcholinesterase (BuChE)] inhibition, among OP-exposed individuals.ObjectivesWe evaluated the relation between plasma PON1 status and BuChE inhibition among OP-exposed agricultural pesticide handlers.MethodsAgricultural pesticide handlers in Washington State were recruited during the 2006 and 2007 spray seasons when they were seen for follow-up ChE testing by collaborating medical providers as part of a statewide monitoring program. Blood samples were collected from 163 participants and tested for PON1 status based on plasma PON1 activity [arylesterase (AREase)] and PON1 Q192R genotype. We evaluated percent change in BuChE activity from baseline level in relation to PON1 status.ResultsWe observed significantly greater BuChE inhibition among QQ homozygotes relative to RR homozygotes (p = 0.036). Lower levels of plasma PON1 activity were significantly associated with greater BuChE inhibition (p = 0.004). These associations remained after adjustment for year, days since baseline test, age, and OP exposure in the last 30 days.ConclusionsWe found that both low PON1 catalytic efficiency (i.e., the Q192 alloform) and low plasma PON1 activity were associated with BuChE inhibition among OP-exposed agricultural pesticide handlers. Corroborative findings from future studies with prospective collection of blood samples for PON1 testing, more sensitive markers of OP-related effects, and larger sample sizes are needed.