TCT-151: Paraoxonase-1 (PON1) Activity And PON1 Polymorphisms Have No Effect On Platelet Reactivity In Patients Treated With Clopidogrel

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.

Download Full-text

Associations between paraoxonase 1 (PON1) polymorphisms and susceptibility and PON1 activity in rheumatoid arthritis patients, and comparison of PON1 activity in patients and controls: a meta-analysis

Clinical Rheumatology ◽

10.1007/s10067-019-04499-0 ◽

2019 ◽

Vol 38 (8) ◽

pp. 2141-2149 ◽

Cited By ~ 6

Author(s):

Sang-Cheol Bae ◽

Young Ho Lee

Keyword(s):

Rheumatoid Arthritis ◽

Meta Analysis ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Pon1 Polymorphisms

Download Full-text

Paraoxonase 1 gene polymorphisms and enzyme activities in diabetes mellitus

Physiological Research ◽

10.33549/physiolres.931285 ◽

2008 ◽

pp. 717-726

Author(s):

M Flekač ◽

J Škrha ◽

K Žídková ◽

Z Lacinová ◽

J Hilgertová

Keyword(s):

Gene Polymorphisms ◽

Diabetes Control ◽

Paraoxonase 1 ◽

High Density Lipoproteins ◽

Pon1 Activity ◽

Diabetic Patients ◽

Restriction Enzyme Digestion ◽

Coding Region ◽

Pon1 Gene ◽

Pon1 Polymorphisms

Paraoxonase 1 (PON1), an antioxidant enzyme closely associated with HDL (high-density lipoproteins), preserves LDL (low-density lipoproteins) against oxidation. Less protection may be therefore supposed by decreased PON1 activity. This study was undertaken to investigate the association of PON1 gene polymorphisms with diabetic angiopathy and to evaluate the relationship of these polymorphisms with PON1 activity. Total of 86 Type 1 (T1DM) and 246 Type 2 (T2DM) diabetic patients together with 110 healthy subjects were examined. DNA isolated from leukocytes was amplified with polymerase chain reaction (PCR) followed by restriction enzyme digestion. The products were analyzed for L55M and Q192R polymorphisms in coding region and for –107 C/T and –907 G/C in promotor sequence of PON1. Serum enzyme activity was measured spectrophotometrically. Significant differences were found between T1DM or T2DM and control persons in L55M polymorphism (allele M more frequent in T1DM and T2DM vs. controls, p<0.05) and Q192R polymorphism (R allele less frequent in T1DM and T2DM vs. controls, p<0.01) of the PON1 gene. Serum PON1 activity was significantly decreased in T1DM (110±68 nmol/ml/min) and T2DM patients (118±69 nmol/ml/min) compared to the control persons (203±58 nmol/ml/min), both p<0.01. The presence of MM and QQ genotypes was accompanied by lower PON1 activity than of LL and RR genotypes (p<0.05), respectively. Better diabetes control was found in patients with LL than with MM genotypes and similarly in RR genotype than QQ genotype with p<0.05. Significantly different allele frequencies were found in diabetic patients with macroangiopathy than in those without it (M: 0.59 vs. 0.44. R: 0.12 vs. 0.19, p<0.01). The association of PON1 polymorphisms, lower PON1 activity and poorer diabetes control found in patients with macroangiopathy further support the idea of genetic factors contributing to the development of vascular disorders in diabetes.

Download Full-text

Abstract P526: PON1 Q192R Alters Clopidogrel Efficacy in Patients With Coiling of Intracranial Aneurysm but Not Carotid Artery Stenting

Stroke ◽

10.1161/str.52.suppl_1.p526 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Koji Tanaka ◽

Shoji Matsumoto ◽

Gulibahaer Ainiding ◽

Ichiro Nakahara ◽

Akira Ishii ◽

...

Keyword(s):

Carotid Artery ◽

Intracranial Aneurysm ◽

Coil Embolization ◽

Carotid Artery Stenting ◽

Platelet Reactivity ◽

Density Lipoprotein ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Loss Of Function ◽

The Impact

Introduction: The impact of the paraoxonase-1 ( PON1 ) polymorphism, Q192R (rs662; c.575A>G or p.Gln192Arg), on platelet inhibition in response to clopidogrel remains controversial. We investigated the impact of PON1 Q192R on post-clopidogrel platelet reactivity in patients undergoing coil embolization for intracranial aneurysm (IA) and carotid artery stenting (CAS). Methods: Between May 2010 and September 2015, 567 patients undergoing elective neurointervention with dual antiplatelet therapy were registered. On-treatment platelet reactivity was measured using a VerifyNow P2Y12 assay in P2Y12 reaction units (PRUs). High platelet reactivity (HPR) was defined as a PRU of ≥208. Genotype testing was performed for PON1 Q192R and CYP2C19*2 and *3 (loss of function alleles), and *17 . Consequently, 473 patients were eligible for further analysis. For patients undergoing coil embolization for IA or CAS, associations between ≥1 PON1 192R allele and HPR were investigated. Results: HPR was observed in 59.4% of 276 patients undergoing coil embolization for IA (78 male; median age, 62 years) and 47.7% of 197 patients undergoing CAS (153 male; median age, 72 years). Among patients undergoing coil embolization for IA, carriers of ≥1 PON1 192R allele demonstrated HPR more frequently compared with non-carriers (92.1% vs. 83.0%, respectively; P = 0.021). Carrying ≥1 PON1 192R allele was associated with HPR (adjusted odds ratio [aOR] 3.43, 95% confidence interval [CI] 1.45-8.42). In contrast, among patients undergoing CAS, the frequency of HPR was similar between carriers of ≥1 PON1 192R allele compared with non-carriers (90.4% vs. 87.4%, respectively; P = 0.652). Carrying ≥1 PON1 192R allele was not associated with HPR (aOR 0.95, 95% CI 0.34-2.60). Conclusions: PON1 Q192R is associated with HPR of clopidogrel in patients undergoing coil embolization for IA but not in patients undergoing CAS. PON1 metabolizes clopidogrel into the inactive endo isomer. By contrast, PON1 protects against low-density lipoprotein oxidation. High PON1 activity may cancel the disadvantage in clopidogrel metabolism through its antioxidant and atheroprotective effects in patients carrying ≥1 PON1 192R allele with carotid artery stenosis representing advanced systemic atherosclerosis.

Download Full-text

Why Should Psychiatrists and Neuroscientists Worry about Paraoxonase 1?

Current Neuropharmacology ◽

10.2174/1570159x17666181227164947 ◽

2019 ◽

Vol 17 (11) ◽

pp. 1004-1020 ◽

Cited By ~ 9

Author(s):

Estefania Gastaldello Moreira ◽

Karine Maria Boll ◽

Dalmo Guilherme Correia ◽

Janaina Favaro Soares ◽

Camila Rigobello ◽

...

Keyword(s):

Clinical Trials ◽

Drug Targets ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Psychiatric Diseases ◽

Physically Active ◽

Effective Strategies ◽

Q192r Polymorphism ◽

Pubmed Database ◽

Pon1 Polymorphisms

Background: Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms. Objectives: 1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities. Methods: The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity. Results: The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity. Conclusion: Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.

Download Full-text

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia

VASA ◽

10.1024/0301-1526/a000643 ◽

2017 ◽

Vol 46 (5) ◽

pp. 370-376 ◽

Cited By ~ 2

Author(s):

Anita Szentpéteri ◽

Noémi Zsíros ◽

Viktória E. Varga ◽

Hajnalka Lőrincz ◽

Mónika Katkó ◽

...

Keyword(s):

Adhesion Molecule ◽

Oxidized Ldl ◽

Vascular Complications ◽

Cd40 Ligand ◽

Paraoxonase 1 ◽

Intercellular Adhesion Molecule ◽

Pon1 Activity ◽

Intercellular Adhesion Molecule 1 ◽

Inflammatory Parameters ◽

Vascular Biomarkers

Abstract. Background: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. Patients and methods: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. Results: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. Conclusions: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

Download Full-text

Intestinal and Hepatic Uptake of Dietary Peroxidized Lipids and Their Decomposition Products, and Their Subsequent Effects on Apolipoprotein A1 and Paraoxonase1

Antioxidants ◽

10.3390/antiox10081258 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1258

Author(s):

Xueting Jiang ◽

Pragney Deme ◽

Rajat Gupta ◽

Dmitry Litvinov ◽

Kathryn Burge ◽

...

Keyword(s):

Cell Culture ◽

Culture Media ◽

Degradation Products ◽

Apolipoprotein A1 ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Atherosclerotic Cardiovascular Disease ◽

Metabolic Fate ◽

Cell Culture Media ◽

Decomposition Products

Both pro- and antiatherosclerotic effects have been ascribed to dietary peroxidized lipids. Confusion on the role of peroxidized lipids in atherosclerotic cardiovascular disease is punctuated by a lack of understanding regarding the metabolic fate and potential physiological effects of dietary peroxidized lipids and their decomposition products. This study sought to determine the metabolic fate and physiological ramifications of 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 13-HODE (13-hydroxyoctadecadienoic acid) supplementation in intestinal and hepatic cell lines, as well as any effects resulting from 13-HPODE or 13-HODE degradation products. In the presence of Caco-2 cells, 13-HPODE was rapidly reduced to 13-HODE. Upon entering the cell, 13-HODE appears to undergo decomposition, followed by esterification. Moreover, 13-HPODE undergoes autodecomposition to produce aldehydes such as 9-oxononanoic acid (9-ONA). Results indicate that 9-ONA was oxidized to azelaic acid (AzA) rapidly in cell culture media, but AzA was poorly absorbed by intestinal cells and remained detectable in cell culture media for up to 18 h. An increased apolipoprotein A1 (ApoA1) secretion was observed in Caco-2 cells in the presence of 13-HPODE, 9-ONA, and AzA, whereas such induction was not observed in HepG2 cells. However, 13-HPODE treatments suppressed paraoxonase 1 (PON1) activity, suggesting the induction of ApoA1 secretion by 13-HPODE may not represent functional high-density lipoprotein (HDL) capable of reducing oxidative stress. Alternatively, AzA induced both ApoA1 secretion and PON1 activity while suppressing ApoB secretion in differentiated Caco-2 cells but not in HepG2. These results suggest oxidation of 9-ONA to AzA might be an important phenomenon, resulting in the accumulation of potentially beneficial dietary peroxidized lipid-derived aldehydes.

Download Full-text

Paraoxonase 1 concerning dyslipidaemia, cardiovascular diseases, and mortality in haemodialysis patients

Scientific Reports ◽

10.1038/s41598-021-86231-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alicja E. Grzegorzewska ◽

Paulina Adamska ◽

Ewa Iwańczyk-Skalska ◽

Kamila Ostromecka ◽

Leszek Niepolski ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Hdl Cholesterol ◽

Protein Product ◽

Paraoxonase 1 ◽

Pon1 Activity ◽

Cerebral Stroke ◽

Adhesion Properties ◽

Cholesterol Ratio ◽

Atherogenic Dyslipidaemia ◽

Uremic Patients

AbstractParaoxonase 1 (PON1) is known for preventing atherosclerosis through lipid-modifying features, antioxidant activity, anti-inflammatory, anti-apoptosis, anti-thrombosis, and anti-adhesion properties. Uremic patients requiring haemodialysis (HD) are especially prone to atherosclerosis and its complications. We analysed the PON1 gene (PON1) polymorphisms and serum PON1 (paraoxonase) activity concerning dyslipidaemia and related cardiovascular diseases and mortality to show how they associate under uremic conditions modified by maintenance HD treatment. The rs662 AA + AG (OR 1.76, 95%CI 1.10–2.80, P = 0.018), rs854560 TT (OR 1.48, 95%CI 1.04–2.11, P = 0.031), and rs854560 AT + TT (OR 1.28, 95%CI 1.01–1.63, P = 0.040) contributed to the prevalence of atherogenic dyslipidaemia diagnosed by the triglyceride (TG)/HDL-cholesterol ratio ≥ 3.8. The normalized serum PON1 activity positively correlated with atherogenic dyslipidaemia (ẞ 0.67 ± 0.25, P = 0.008). The PON1 rs854560 allele T was involved in the higher prevalence of ischemic cerebral stroke (OR 1.38, 1.02–1.85, P = 0.034). The PON1 rs705379 TT genotype contributed to cardiovascular (HR 1.27, 95% CI 1.03–1.57, P = 0.025) and cardiac (HR 1.34, 95% CI 1.05–1.71, P = 0.018) mortality. All P-values were obtained in multiple regression analyses, including clinical variables. Multifaceted associations of PON1 with dyslipidaemia, ischemic cerebral stroke, and cardiovascular mortality in HD patients provide arguments for the consideration of PON1 and its protein product as therapeutic targets in the prevention of atherosclerosis and its complications in uremic patients.

Download Full-text