The Antioxidant Enzyme PON1: A Potential Prognostic Predictor of Acute Ischemic Stroke

Objective. Paraoxonase 1 (PON1) is an antioxidant enzyme, which has been proved to be involved in the pathophysiological process of oxidative stress and various neurological diseases in recent years. Although reduced PON1 activity has been reported in patients with acute ischemic stroke (AIS), the prognostic value of PON1 in AIS has not been clearly established. The purpose of this study was to determine whether the baseline serum PON1 activity level is related to the functional outcome of AIS patients. Methods. From July 2017 to June 2020, AIS patients within 3 days of symptom onset were continuously prospectively included in the study. On admission, clinical and laboratory data were recorded, and serum PON1 activity was tested. The National Institute of Health Stroke Scale (NIHSS) score was used to evaluate the initial neurologic deficit at admission, and the modified Rankin scale (mRS) was used to evaluate the functional outcome at 3 months. A multiple logistic regression model was used to analyze the relationship between the baseline PON1 activity level and the prognosis of AIS. Results. A total of 336 AIS patients were finally included in this study. The serum PON1 activity of AIS patients with good outcomes was significantly higher than that of patients with poor outcomes ( 193.4 ± 16.3 U / mL vs. 127.2 ± 14.9 U / mL , p < 0.001 ). However, the comparison of other clinical and laboratory data between AIS patients with good and poor outcomes was not significant ( p > 0.05 ). There was a significant decrease in the mRS score in patients with AIS across serum PON1 quartiles ( 3.0 ± 1.6 , 2.6 ± 1.5 , 2.4 ± 1.4 , and 2.4 ± 1.3 , p = 0.007 ). Multivariate logistic regression analysis showed that the 3-month functional outcome of AIS patients was significantly correlated with the quartile of serum PON1 activity. Conclusions. This study suggests that the serum PON1 activity may be an independent predictor of the functional outcome of AIS patients.

Association of PON1 gene polymorphisms and enzymatic activity with risk of coronary artery disease

Background: The present case–control study evaluated the association of PON1 gene polymorphisms and enzyme activity in the western Indian population. Materials & methods: Angiographically proven coronary artery disease (CAD) formed the cases. PON1 polymorphisms (Q192R, L55M) and enzymatic activity (paraoxonase) were assessed. Results: A total of 502 participants (251 per group) were studied. PON1 Q192R and L55M polymorphisms were not associated with the risk of CAD. Notably, a weak association was observed between Q192R polymorphisms and the risk of CAD. CAD patients had significantly lower PON1 enzymatic activity (U/L) as compared with the controls regardless of the genotype. Conclusion: Low serum PON1 activity was confirmed to be an independent predictor for the risk of CAD.

P1275PARAOXONASE 1 (PON1) GENE POLYMORPHISMS, PON1 EXPRESSION IN PBMCS, AND SERUM PON1 ACTIVITY CONCERNING DYSLIPIDEMIA AND RELATED COMORBIDITIES IN HEMODIALYSIS (HD) PATIENTS

Background and Aims PON1 may prevent atherosclerosis influencing lipid metabolism and exerting antioxidant and anti-inflammatory activities. We focused on serum PON1 activity in HD patients concerning dyslipidemia, coronary heart disease (CHD), myocardial infarction (MI), and cerebral stroke (CS). PON1 activity was related to PON1 polymorphisms, PON1 expression in PBMCs, and demographic, clinical, and laboratory data. Method In 93 HD patients (men 55, age 66.7, 18.3 – 86.2 years, renal replacement therapy duration 3.9, 0.2 – 22.3 years, CHD 25, MI 15, CS 9), dyslipidemia was diagnosed by K/DOQI guidelines. The TG/HDL-cholesterol ratio of ≥3.8 indicated atherogenic dyslipidemia. Standard diagnostic rules were applied for CHD, MI, and CS recognition. PON1 activity was measured in serum using an automated PON1 assay kit. PON1 polymorphisms were genotyped by high-resolution melting curve analysis (rs662) or using predesigned TaqMan SNV Genotyping Assay (rs854560 and rs705379). In 46 subjects, the relative PON1 transcript level was determined in PBMCs using reverse transcription-quantitative polymerase chain reaction analysis. Results In univariate analyses, the lower serum PON1 activity the higher frequency of mixed dyslipidemia (LDL ≥ 100 mg/dL, TG ≥ 200 mg/dL, non-HDL ≥ 130 mg/dl; β ± SE: -21.4 ± 10.0, P = 0.035) and the higher serum TG levels (β ± SE: -1.06 ± 0.49, P = 0.034). Normalized serum PON1 activity (the PON1/HDL ratio) correlated positively with male sex (β ± SE: 0.56 ± 0.25, P = 0.029), atherogenic dyslipidemia (β ± SE: 0.67 ± 0.25, P = 0.008), and cigarette smoking (β ± SE: 0.86 ± 0.42, P = 0.043). After adjustment for gender, cigarette smoking, urine output, living in rural area, and serum phosphorus, significance was maintained between normalized serum PON1 activity and atherogenic dyslipidemia (β ± SE: 0.54 ± 0.24, P = 0.028), male sex (β ± SE: 0.51 ± 0.24, P = 0.037) and cigarette smoking (β ± SE: 0.93±0.41, P = 0.024) as well as revealed for living in rural area (β ± SE: 0.55 ± 0.26, P = 0.039), urine output (β ± SE: -0.14 ± 0.07, P = 0.046), and zinc supplementation (β ± SE: 1.5 ± 0.67, P = 0.029). PON1 activity (101, 27.7 – 213 U/L) and normalized PON1 activity (2.27, 0.57 – 7.10) were not influenced by PON1 polymorphisms and did not yield differences in patients stratified by CHD, MI, CS, and dyslipidemic patterns except atherogenic dyslipidemia. The latter relationship was caused by a correlation between serum PON1 activity and TG (r = -0.220, P = 0.034). PON1 transcript was detected in PBMCs of 9 subjects. They showed a higher prevalence of the AG + GG genotypes of PON1 rs662 (77.8% vs. 34.3%, P = 0.027), a higher serum CRP level (7.8, 2.8 – 46.8 mg/L vs. 3.9, 0.4 – 23.0 mg/L, P = 0.042), and a lower albumin (3.9, 2.6 – 4.5 g/dL vs. 4.2, 3.2 – 4.6 g/dL, P = 0.025) compared with the results of 37 subjects without the PON1 expression. The relative PON1 transcript level did not correlate with serum PON1 activity (r = 0.042, P = 0.915). Conclusion In HD patients, serum PON1 activity is associated with atherogenic dyslipidemia but not with already developed CHD and history of MI or CS, even after adjustment for several confounding variables. Illegitimate PON1 transcription occurs in uremic PBMCs at very low level and is influenced by PON1 rs662 polymorphism and upregulated by inflammation. PON1 could be considered as a therapeutic target in prevention of atherosclerosis and its complications in uremic patients.

Paraoxonase-1 Enzyme Activity and Oxidative Status in Pulmonary Hypertension Original Article

Objective: Oxidative stress has been considered to be one of the main causes for the development of pulmonary hypertension (PH) via leading alteration of pulmonary vasomotor tone induced by hypoxia. The aim of this study is to determine the serum paraoxonase-1 enzyme (PON-1) activity, arylesterase activity, the antioxidant-oxidant status in patients with PH and to compare with healthy controls. Material and Methods: Thirty five healthy ındividuals (mean age 45.7±5.9 years) as a control group and thirty eight patients (mean age 46.5±12.6 years) with a diagnosis of PH wereincluded in thestudy. Serum PON-1 and arylesterase activity, the total antioxidative capacity of plasma (TAC) and total oxidantstatus (TOS) were measured by using colorimetric methods. The Oxidative Stress Index (OSI) wascalculated as TOS/ TACX100. Results: Serum PON1 activity is significantly lower in PH patients when compared with healthy controls (p=0.001). The serum arylesterase activity and TAC, TOS and OSI status were similarin bothgroups. There is inverse correlation between serum PON1 activityand NYHA functionalcapacity (r:-0.649 p=0.001). Furthermore, PON1 activity of study patients are similarin the PH subgroups. Serum activity of PON1 wasfoundto bethe only independent parameter for the presence of PH in binary logistic regression analysis (OR 0.984, 95 % CI 0.977-0.992, p=0.001). Eight patients died follow up period (27.6±14.5 months) and none of theparametersincluding PON1 were associated with mortality. Conclusion: Serum PON1 activity of PH patients is lowerthanhealthypopulation, but does not predictmortality. Bangladesh Journal of Medical Science Vol.19(4) 2020 p.652-658

Low Serum Paraoxonase-1 Activity Associates with Incident Cardiovascular Disease Risk in Subjects with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein

Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker of low-grade systemic inflammation. Cox proportional-hazards modeling of incident CVD risk (11 years mean follow-up) adjusted for relevant clinical and biomarker covariates was performed on a population-based study (N = 7766) stratified into three groups: low CRP—(LR; event rate 4.9%); low HDL-C/high CRP—(HR1; event rate 14.4%); and high HDL-C/high CRP—(HR2; event rate 7.6%). Modeling results for PON1 activity in HR2 were significant and robust (hazard ratio/SD unit—0.68, 95% CI 0.55–0.83, p = 0.0003), but not so for LR and HR1. Analyses in HR2 of the interaction of PON1 with HDL-C, apoA-I, apoA-II, and apoE levels were significant only for PON1 with apoE (hazard ratio—1.77, 95% CI 1.29–2.41, p = 0.0003). Subsequent subgroup analysis revealed inverse risk dependence for apoE at low PON1 levels. In conclusion, in a population-based study of subjects with concurrently high HDL-C and CRP levels, low serum PON1 activity associates with incident CVD risk with risk accentuated at low apoE levels.

Paraoxonase activity an indicator of complications at early stage of complicated pregnant cows

In healthy and complicated pregnant cows, on the 2nd and 6th months of pregnancy in order to determine the levels of maternal serum Paraoxonase 1 (PON1) activity and the possibility of complications can occur during the pregnancy might be a premise indication. Serum samples were taken at 2nd and 6th months of 252 pregnant cows at the end of their pregnancies. The cows were classified into two groups such as complicated (Abortion, Dystocia) and non-complicated. Maternal serum PON1 activity in 6th months was lower at complicated group than normally pregnant group (P=0.004; P less than 0.01), no difference was discovered between these groups in their 2nd month of pregnancy (P>0.05). Among the concentration of HDL, TP and globulin no statistical difference was observed between complicated, subgroups and normal births (P>0.05). Levels of PON1 in 2 and 6 months were statistically different between the groups of dystocia and normal pregnancy (P less than 0.01; P = 0.003), and abort and normal pregnancy (P less than 0.05; P=0.033). In this study, it was inferred that the evaluation of PON1 activity early indicator of complications for clinicians that might occur in further periods of pregnancy. These results showed the fact that PON1 activity can be used as a marker relatively at the early phases of pregnancy in complicated cows.

Investigation of paraoxonase 1 activity of the workers at the plant, who have long-term contact with organophosphorus compounds

Background. Liver enzyme paraoxonase 1 (PON1) plays an important role in protection the organism from toxic effects of organophosphorus compounds (OPs) via their hydrolysis whose rate and efficiency depend on PON1 serum level activity. PON1 activity is largely determined by the polymorphic variants of the PON1 gene. Effect of long-term work with exposure to the toxic OPs on the PON1 activity is almost unknown. The aim of the present work was to study the effect of long-term work with exposure to the toxic OPs on PON1 serum enzymatic activity depending on polymorphisms Q191R, L54M, C(-108)T PON1 gene. Materials and methods. PON1 serum enzymatic activity and PON1 polymorphisms were determined in men, who were categorized in 2 groups: workers of companies providing storage and disposal of the OPs (68) and control group (37). The PON1 191, PON1 55 and PON1 108 polymorphisms were studied by polymerase chain reaction/restriction fragment length polymorphism. PON1 serum enzymatic activity was measured by a spectrophotometric method using paraoxon. Results. PON1 activity in workers with exposure to the toxic OPs relative was increased compared to the control group (p = 0,027). Differences in serum PON1 activity was shown for the carriers of certain genotypes of the PON1 gene: PON1 serum activity was higher in workers compared to controls only for LL genotype (L54M polymorphism) and C allele (C(-108)T polymorphism) carriers (p < 0,001 and p = 0,002, correspondently). Conclusion. We suggest that the increase in serum PON1 activity in workers providing storage and disposal of OPs could be modulated with the polymorphic variants of the PON1 gene.

Acetaminophen intoxication is associated with decreased serum paraoxonase and arylesterase activities and increased lipid hydroperoxide levels

Background: Acetaminophen is at present one of the most commonly used analgesics and antipyretics. Recent evidence has suggested that oxidative stress is involved in the mechanism of acetaminophen intoxication. 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 acetaminophen intoxication. Methods: A total of 20 patients with acetaminophen intoxication and 25 healthy controls were enrolled. Serum total antioxidant capacity (TAC), lipid hydroperoxide (LOOH) levels, and paraoxonase and arylesterase activities were measured spectrophotometrically. Results: The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower in patients with acetaminophen intoxication compared with controls (all, p < 0.001), while the serum LOOH levels were significantly higher ( p < 0.001). Conclusions: Our results suggest that decreased PON1 activity seems to be associated with increased oxidative stress in patients with acetaminophen intoxication. Measuring serum PON1 activity may be useful in assessing the development of toxicity risk in acetaminophen toxicity. It would be useful to recommend vitamins with antioxidant effects such as vitamins C and E along with medical treatments.