Paraoxonase-1 Status Research Articles

Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery—A Randomized, Controlled Clinical Trial

ObjectivesCardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role, whose activity is decreased in systemic inflammation, and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by up-regulating PON1 gene expression. We aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DesignProspective, randomized, controlled clinical trial. SettingThe study was conducted at the University Medical Centre Ljubljana, Slovenia. Participants40 adult patients, who underwent complex cardiac surgery on CPB between February 2016 and December 2017, were randomized into methylprednisolone and control group (n=20 each). InterventionsPatients in the methylprednisolone group received 1g of methylprednisolone in the CPB priming solution, while patients in the control group were not given methylprednisolone during CPB. Measurements and Main ResultsWe compared the effect of methylprednisolone from CPB priming solution with standard care during CPB on PON1 activity until the 5. postoperative day. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed as well. No significant differences existed between study groups for PON1 activity, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in any of the measurement intervals (p>0.016). Methylprednisolone group had significantly lower TNF-a (p<0.001), IL-6 (p<0.001), as well as CRP and procalcitonin (p<0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and TNF-a, IL-6, as well as CPB duration. ConclusionsMethylprednisolone doesn't influence PON1 activity during cardiac surgery on CPB.

Effect of Carotenoids on Paraoxonase-1 Activity and Gene Expression.

Paraoxonase 1 (PON1) is an antioxidant enzyme attached to HDL with an anti-atherogenic potential. It protects LDL and HDL from lipid peroxidation. The enzyme is sensitive to various modulating factors, such as genetic polymorphisms as well as pharmacological, dietary (including carotenoids), and lifestyle interventions. Carotenoids are nutritional pigments with antioxidant activity. The aim of this review was to gather evidence on their effect on the modulation of PON1 activity and gene expression. Carotenoids administered as naturally occurring nutritional mixtures may present a synergistic beneficial effect on PON1 status. The effect of carotenoids on the enzyme depends on age, ethnicity, gender, diet, and PON1 genetic variation. Carotenoids, especially astaxanthin, β-carotene, and lycopene, increase PON1 activity. This effect may be explained by their ability to quench singlet oxygen and scavenge free radicals. β-carotene and lycopene were additionally shown to upregulate PON1 gene expression. The putative mechanisms of such regulation involve PON1 CpG-rich region methylation, Ca(2+)/calmodulin-dependent kinase II (CaMKKII) pathway induction, and upregulation via steroid regulatory element-binding protein-2 (SREBP-2). More detailed and extensive research on the mechanisms of PON1 modulation by carotenoids may lead to the development of new targeted therapies for cardiovascular diseases.

Reduced paraoxonase 1 activities may explain the comorbidities between temporal lobe epilepsy and depression, anxiety and psychosis.

BACKGROUNDTemporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase 1 (PON1) status may occur in TLE and these psychiatric conditions. AIMTo examine PON1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in TLE.METHODSWe recruited 40 normal controls and 104 TLE patients, 27 without comorbidities and 77 with comorbidities including mood disorders (n = 25), anxiety disorders (n = 27) and psychosis (n = 25).RESULTSFour-(chloromethyl)phenyl acetate hydrolysis (CMPAase) and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than those in normal controls. The areas under the receiver operating characteristic curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (± 0.037) for MTS. Partial least squares path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (P < 0.0001) and psychopathology (P < 0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination score. CONCLUSIONThe severity of TLE and comorbidities are to a large extent explained by reduced PON1 enzyme activities and by effects of the Q192R genotype, which are mediated by reduced CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.

The Role of Nutritional Habits and Moderate Red Wine Consumption in PON1 Status in Healthy Population

Paraoxonase 1 (PON1) plays a role as antioxidant on HDL. Including in diet additionally ingest of polyphenolic compounds can stimulate PON1 transcription and increase its activity. The aim of this study was to evaluate the effect of dietary intake, red wine consumption, and PON1 genotypes (Q192R, L55M and C-108T) on the specific activity of PON1 in a healthy population. A descriptive and analytical pilot study was conducted in Mexican volunteers clinically healthy (n = 45) aged from 21–59 years. Over 6 weeks, the study participants ingested 120 mL of red wine per day. PON1 concentration, PON1 activities, genetic polymorphisms and dietary intake were evaluated. The preliminary fingerprinting of the wine was determined to corroborate the presence of phenolic compounds such as tannins and gallotannins. Neither dietary intake nor PON1 genotypes showed an effect on the specific activity of PON1. However, a significant increase in specific AREase activity after red wine consumption period was observed in the study participants. Our data suggest that the moderate consumption of red wine has a beneficial effect on PON1 specific AREase activity in this healthy Mexican population.

A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease

BackgroundThe multifactorial nature of non-alcoholic fatty liver disease cannot be explained solely by genetic factors. Recent evidence revealed that DNA methylation changes take place at proximal promoters within susceptibility genes. This emphasizes the need for integrating multiple data types to provide a better understanding of the disease’s pathogenesis. One such candidate gene is paraoxonase-1 (PON1). Substantial interindividual differences in PON1 are apparent and could influence disease risk later in life. The aim of this study was therefore to determine the different regulatory aspects of PON1 variability and to examine them in relation to the predisposition to obesity-associated fatty liver disease.ResultsA targeted multi-omics approach was applied to investigate the interplay between PON1 genetic variants, promoter methylation, expression profile and enzymatic activity in an adult patient cohort with extensive metabolic and hepatic characterisation including liver biopsy. Alterations in PON1 status were shown to correlate with waist-to-hip ratio and relevant features of liver pathology. Particularly, the regulatory polymorphism rs705379:C > T was strongly associated with more severe liver disease. Multivariable data analysis furthermore indicated a significant association of combined genetic and epigenetic PON1 regulation. This identified relationship postulates a role for DNA methylation as a mediator between PON1 genetics and expression, which is believed to further influence liver disease progression via modifications in PON1 catalytic efficiency.ConclusionsOur findings demonstrate that vertical data-integration of genetic and epigenetic regulatory mechanisms generated a more in-depth understanding of the molecular basis underlying the development of obesity-associated fatty liver disease. We gained novel insights into how NAFLD classification and outcome are orchestrated, which could not have been obtained by exclusively considering genetic variation.

Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment.

Background:Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer’s disease.Objective:We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI).Methods:Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates.Results:In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition.Conclusion:PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

Paraoxonase-1 (PON1) Status Analysis Using Non-Organophosphate Substrates.

Human paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme with antioxidant, anti-inflammatory, and antiapoptotic roles. The ability of PON1 to hydrolyze specific organophosphate (OP) compounds and prevent accumulation of oxidized lipids in lipoproteins has prompted a large number of studies investigating PON1's role in modulating toxicity and disease. Most of these studies, however, have only focused on PON1 single nucleotide polymorphism analyses and have ignored PON1 activity levels, arguably the most important parameter in determining protection against exposure and disease. We developed a two-substrate activity assay termed "PON1 status" that reveals both the functional PON1192 genotype and plasma PON1 activity levels. While our previous studies with PON1 status demonstrated that both PON1192 functional genotype and enzymatic activity levels obtained exclusively by determining PON1 status are required for a proper evaluation of PON1's role in modulating OP exposures and risk of disease, the original PON1 status assay requires the use of highly toxic OP metabolites. As many laboratories are not prepared to handle such toxic compounds and the associated waste generated, determination of PON1 status has been limited to rather few studies. Here, we describe a PON1 status protocol that uses non-OP substrates with a resolution equivalent to that of the original PON1 status approach. We have also included useful suggestions to ensure the assays can easily be carried out in any laboratory. The protocols described here will enable a proper examination of the risk of exposure or susceptibility to disease in PON1 epidemiological studies without the need to handle highly toxic substrates. © 2021 Wiley Periodicals LLC. Basic Protocol: Determining PON1 status using non-organophosphate substrates Support Protocol 1: Experimental pathlength determination Support Protocol 2: PON1 DNA genotyping for the Q192R (rs662) polymorphism.

Paraoxonase 1 Phenotype and Protein N-Homocysteinylation in Patients with Rheumatoid Arthritis: Implications for Cardiovascular Disease.

Paraoxonase 1 (PON1) is the high density lipoprotein-associated esterase which inhibits the development of atherosclerosis by metabolizing lipid peroxidation products as well as hydrolyzing proatherogenic metabolite of homocysteine (Hcy), Hcy thiolactone, which otherwise reacts with lysine groups of proteins, thus forming N-Hcy-protein in a process referred to as protein N-homocysteinylation. Rheumatoid arthritis (RA) is the chronic inflammatory autoimmune disease associated with increased risk of cardiovascular complications, but the underlying mechanisms are incompletely understood. We examined PON1 status and N-homocysteinylation of serum proteins in patients with RA. Blood was collected from 74 RA patients and 70 control subjects. PON1 activity was measured toward synthetic (paraoxon, phenyl acetate) and natural (Hcy thiolactone) substrates. PON1 protein concentration was measured by ELISA. Total Hcy as well as N-Hcy-protein were measured in serum as well. PON1 activity toward Hcy thiolactone was lower in RA patients than in control subjects which was accompanied by increased concentration of N-Hcy-protein despite normal total Hcy concentration. PON1 protein concentration was unchanged in the RA group, but the specific enzyme activity was reduced. When RA patients were categorized according to the DAS28-ESR score, PON1 concentration and enzymatic activity were lower whereas N-Hcy-protein was higher in those with high disease activity. PON1 activity and Hcy thiolactone were correlated with DAS28-ESR score and myeloperoxidase concentration. In conclusion, RA is associated with deficiency of PON1 activity and increased protein N-homocyseinylation which may contribute to accelerated development of cardiovascular diseases.

PON1 status and homocysteine levels as potential biomarkers for cardiovascular disease.

Cardiovascular disease (CVD) is the leading cause of death. The mainly risks factors for CVD are diabetes, hypertension and high levels of homocysteine (Hcys), among others. Paraoxonase 1 (PON1) has been proposed as an antiatherogenic target for its ability to hydrolyzing oxi-Low-Density-Lipoproteins (LDL) and Hcys-thiolactone. Thus, the aim of the present study was to evaluate the association of Hcys levels, and the activities and concentration of PON1, as well as vitamin B from the diet with a risk for CVD. A case-control study was carry out in patients with cardiovascular diseases (CVD), Arterial hypertension, but not CVD (AH), and in healthy controls (control group) from the Mexican Institute of Social Security. Lipid profile, intake of vitamin B, Hcys, serum amyloid A (SAA), PON1 concentration, and PON1 activities (Arylesterase activity (ARE), Lactonase activity (LAC), and CMPA activity (CMPA)) were evaluated. The CVD group had the highest concentration of Hcys and SAA than in the AH and control groups (p<0.01). ARE, LAC, and CMPA activities and PON1 concentration were lowest in the CVD group. A positive-independent association between Hcys levels and CVD was found (OR=2.09; 95% CI: 1.69-2.56) and this increase when it was adjusted by age, BMI, ApoA1, vitamin B intake, SAA, and PON1 (OR=14.41; 95% CI: 1.75-118.71). LAC and CMPA, as well as PON1 concentration, were inversely associated with CVD. LAC activity, PON1 concentration, and Hcys levels might be good biomarkers for CVD and their association could be modified by the intake of vitamin B.

Paraoxonase 1 and atherosclerosis-related diseases.

A direct and an indirect relationship between paraoxonase 1 (PON1) and atherosclerosis exists. Given PON1's physical location within high-density lipoprotein (HDL) particles and its recognized enzyme activity, it is certainly reasonable to suggest that PON1 facilitates the antiatherogenic nature of HDL particles. PON1 also plays a role in regulating reverse cholesterol transport, antioxidative, anti-inflammatory, antiapoptotic, vasodilative, and antithrombotic activities and several endothelial cell functions. HDL dysfunctionality is a more recent issue and seems to be centered on pathological conditions affecting HDL structure and size profiles. This review is focused on the role of PON1 status in different atherosclerosis-related diseases that we have studied over the last twenty years (coronary heart disease, acute ischemic stroke, diabetes mellitus type 2, end-stage renal disease, chronic obstructive pulmonary disease, and sarcoidosis) with the aim to determine the true value of PON1 as a biomarker. The role of PON1 in cancer is also covered, as risk factors and mechanisms underlying both atherosclerosis and cancer share common features.

PON1 concentration and high-density lipoprotein characteristics as cardiovascular biomarkers.

IntroductionSerum paraoxonase 1 (PON1) is now known to be related to cardiovascular diseases (CVD). The aim of this study was to determine the relationship between PON1 concentration and high-density lipoprotein (HDL) subclasses in patients with proven CVD, cardiovascular risk factors but no CVD (CRF), and in healthy controls (control group).Material and methodsA case-control study was carried out with 69 volunteers from the Mexican Institute of Social Security, Mexico. Clinical parameters, lipid profile, PON1 concentration, PON1 activities (AREase and CMPAase), and HDL subclasses were evaluated.ResultsPatients with CVD had significantly higher glucose and lower total cholesterol than the control group had (p < 0.01). AREase activity was not different between the control (122.57 ±30.72 U/ml), CRF (115.81 ±32.81 U/ml), and CVD (109.34 ±29.60 U/ml) groups. PON1 concentration was significantly lower in CVD patients than in CRF and control patients (p < 0.001); a positive correlation was observed between AREase activity and PON1 concentration in the CVD group (Rho = 0.58; p < 0.01). Logistic regression analysis showed that the decrease in PON1 level was associated with the CVD group (RRR = 0.20; 95% CI: 0.09–0.45) but not with the CRF group (RRR = 1.29; 95% CI: 0.89–1.90). Significant differences were observed in HDL 2a and HDL 3a concentrations between the control group and CRF and CVD groups (p < 0.05), but not between the CRF and CVD groups.ConclusionsOur data suggest that PON1 status and HDL characteristics could be early biomarkers that predict the potential for developing CVD.

Paraoxonase-1 genetic polymorphisms in organophosphate metabolism

Organophosphates (OPs) are a class of chemicals commonly used in agriculture as pesticides, that can often lead to severe toxicity in humans. Paraoxonase-1 (PON1) belongs to a family of A-esterases and hydrolyses several OPs while also serving other biological roles. Two main genetic polymorphisms have been shown to affect enzymatic ability; an A > G transition in the 192nd position (192 Q/R, rs662), and an A > T at codon 55 (55 M/L, rs854560). In this review, we searched PubMed for relevant articles published from its inception till June 2018 and included publications from 1996 to 2018. We aimed to address the distribution of the polymorphisms in various populations, the way they affect enzymatic activity and the possible use of PON1 as a biomarker. The polymorphisms present great heterogeneity between populations, with the data being clearer over 192 Q/R, and this heterogeneity is related to the phylogenetic origins of each population. Concerning enzymatic activity, the different genotypes react better or worse to different OP substrates, with studies presenting a variety of findings. Detecting the “paraoxonase status” of an individual -referring to PON1 function- seems to be important in predicting OP toxicity, as studies have shown that some specific-genotype individuals present symptoms of toxicity in higher rates than others. We are strongly convinced that in order for the scientific community to reach a consensus over which polymorphisms confer susceptibility to toxicity and whether PON1 can eventually be used as a biomarker, more studies need to be carried out, since the data thus far does not seem to reach a universal conclusion.

Changes in lipid profile parameters and PON1 status associated with L55M PON1 polymorphism, overweight and exposure to tobacco smoke

Objective: The aim of our study was to investigate the effects of paraoxonase 1 (PON1) L55M polymorphism on the enzyme’s activity and concentration in the serum as well as its association with lipid profile parameters in a group of healthy persons. We also evaluated the presence of PON1 L55M polymorphism in a group of subjects exposed to tobacco smoke and with overweight or obesity on those parameters. Methods: Analysis of L55M polymorphism was done using polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (PCR – RFLP). Serum PON1 concentration and lipid profile parameters were assayed using commercial tests. PON1 activities were measured earlier elaborated procedures. Results: We observed a statistically significant difference in HDL and PON1 concentration: the highest in the LL genotype and the lowest in the MM genotype with the LM genotype having an intermediate concentration. L55M polymorphism influence on PON1 arylesterase and phosphotriesterase activity, whereas PON1 lactonase activity did not differ in all polymorphic variant groups. Exposure to tobacco smoke and overweight or obesity additionally disorder above mentioned parameters. Overweight and obesity in LM and MM genotype could be associated with higher PON1 phosphotriesterase activity. It is also possible that MM genotype could be a determinant of smoking addiction. Conclusions: L55M polymorphism, like exposure to tobacco smoke and overweight, disorders PON1 status and lipid profile parameters; therefore, it could be a crucial risk factor for the development of many metabolic disorders.

Substrates for Paraoxonase.

Paraoxonase (PON) is a family of calcium-dependent hydrolases, which is related to many diseases. Elucidation of PON physiological roles, active center and all applications in medical fields are dependent on its substrates. The reports about PON substrates scattered in a long span of period are collected to afford clue for drug design, diagnosis of PON status and other academic purposes. PON substrates from 133 references are classified and compared. Structurally, PON substrates are generally classified as organic phosphorous esters, lactones and arylesters. Some phosphoramidates, organophosphorous obidoximes, aryl carboxylic acid amides and special fatty alcohol esters as PON substrates are also included. The electron nature, steric hindrance and hydrophilicity of substrate substituents affecting the PON catalytic ability, binding ability and specificities are discussed. Drugs, prodrugs and naturally endogenous molecules in life processes activated or inactivate by PON are reviewed. Interestingly, some organophosphate and lactone substrates are preferably hydrolyzed by one of the PON1R192Q allozymes, and such a substrate is generally essential for differentiating the three PON1192R phenotypes by using a dual-substrate method. Intricately, some chiral substrates are hydrolyzed by PON stereoselectively. As more substrates are synthesized and characterized, more facts about PON structure and catalytic properties (including PON active center and catalytic mechanism) will be revealed, and therefore the use of PON as a drug target or as an accurate disease marker will be achieved.

Genotype-phenotype Analysis of Paraoxonase 1 in Schizophrenic Patients Treated with Atypical Antipsychotics.

ObjectiveRecent studies suggest a possible involvement of low paraoxonase 1 (PON1) enzyme activities in the association between schizophrenia, treatment with atypical antipsychotics and increased cardiovascular (CVD) risk. In the present study, we aimed at investigating the PON1 status in a group of schizophrenic patients treated with either olanzapine or other antipsychotic, as compared to a group of healthy control participants.MethodsWe assessed the arylesterase (AREase) and paraoxonase (POase) activities of PON1, as well as three common polymorphisms of PON1 gene (Q192R, L55M, −108C>T).ResultsWe found significantly lower (−13.3%) AREase activity in schizophrenic patients, along with significantly lower (−18.2%) POase activity in olanzapine-treated patients with QQ genotype. Furthermore, we found a significant difference between groups in L55M polymorphism distribution, whereas Q192R and −108C>T polymorphisms distributions were similar.ConclusionWe identified the olanzapine-treated patients with QQ genotype as having the lowest PON1 (POase) activity, providing a possible way of identifying schizophrenic patients exposed to the greatest risk of CVD.

Plasma Metabolome, PON1 Status, Environmental Exposures and Childhood Autism

BackgroundFew studies have examined Autism Spectrum Disorder (ASD) and the interplay between genetics and environmental factors. The paraoxonase 1 (PON1) gene regulates the breakdown of organophosphate (OP) pesticides in the body and serves as an important antioxidant. PON1 levels may be affected by single nucleotide polymorphisms (SNPs), therefore individuals with certain PON1 SNPs plus environmental exposure during pregnancy may be at an increased risk for having a child with autism.ObjectiveThe objective of this study was to examine a possible gene‐environment interaction that focuses on prenatal environmental exposures and child metabolic vulnerability as a consequence of polymorphisms in the PON1 gene.MethodsAll children (n=400) in the present study including children with Autism Spectrum Disorder (ASD; n=200), and typically developed control children (TD; n=200) are part of a large ongoing population based case‐control CHARGE (CHildhood Autism Risk from Genetics and Environment) Study. Blood plasma metabolome profiles were obtained by Nuclear Magnetic Resonance (NMR) spectroscopy. Untargeted metabolomics analysis using Chemomx NMR Suite 8.1 was used to identify and quantify 69 metabolites in each sample including amino acids, organic acids, sugars and other compounds. The concentration of PON1 was determined by ELISA kits (Cloud‐Clone Corp), and paraoxonase activity was measured using commercially available assay kits (Molecular Probes Inc.). SNP data and environmental exposure data were previously collected in the CHARGE Study.ResultsChildren with ASD had higher levels of lactate, a metabolic waste product, and higher levels of the amino acids: alanine, serine, glycine, and tryptophan, consistent with mitochondrial dysfunction, and altered energy metabolism. In addition, ASD was associated with higher levels of uridine, a component of RNA previously reported to be inversely correlated with methylation capacity. Although we did not find a significant difference in the PON1 concentration and paraoxonase activity of children with ASD compared to controls, we did find that PON1 SNPs in coding and non‐coding regions significantly affected its plasma concentrations. Moreover, there were a disproportionate number of children with ASD and specific PON1 SNPs that correlated with maternal organophosphate exposures.ConclusionOur results add to the growing body of literature indicating autism is associated with an altered metabolic state compared to typically developed controls. These results suggest that maternal environmental exposures during pregnancy in combination with genetics may impact a child's metabolic outcome. Further studies are needed to understand how the metabolome affects neurodevelopmental outcome, or conversely if neurodevelopmental outcome affects the metabolome.Support or Funding InformationThis study was funded by the NIH 1P30 ESO23513‐01A1 pilot grant, the Administrative Supplement to the CHARGE Study R01 ES015359, and the USDA National Institute of Food and Agriculture Hatch Project 1005945.

Paraoxonase 1 gene polymorphism and enzymatic activity as a prognostic marker in cases of poisoning by cholinesterase inhibitor pesticides among Egyptians

Paraoxonase1 (PON1) is a high-density lipoprotein associated A-esterase capable of hydrolysing activated metabolites (oxons) of several pesticides as organophosphorous, including chlorpyrifos, diazinon as well as carbamates. Human PON1 displays polymorphisms in the coding region (Q192R and L55M) and in the promoter and the 3’-UTR regions. Animal studies showed that high levels of PON1 protect individuals against acute organophosphatespoisoning. The PON1 genotype and enzymatic activity together contribute to determining an individual's PON1 “status”. In this study, the role of PON1 gene polymorphismsand its enzymatic activity was assessed as a prognostic marker in cases of acute poisoning by cholinestersase inhibitor (ChEI) pesticides among a sample of Egyptian population. Two equal groups of 100 unrelated individuals participated in the study: an exposed group and non-exposed group as control. Serum paraoxonase1 enzyme activitymeasured as arylesterase activity spectrophotometrically using the substrate phenyl acetate. PON1 Q192R gene was genotyped using PCR-RFLP technique. The PON1 Q192R genotype frequency distribution in control subjects was (QQ=64%, QR=28%, RR=8%) and in patients was (QQ=54%, QR=42%, RR=4%) and this was statistically significant (p=0.029). The arylesterase activity was significantly higher in control than exposed group (p=0.037). Regarding the effect of Q192R genotype and arylesterase activity on the outcome, there was no significant difference between the good and poor prognosis groups. Evaluation of PON1 status may be important for determining individual susceptibility to poisoning by ChEI pesticides. However, the estimated level of arylesterase after exposure to poisoning can’t be used in prediction of prognosis. Moreover, the coding genes show discrepant results even within the same ethnic group.

Pharmacological Interactions of Paraoxonase 1 (PON1): A HDL-Bound Antiatherogenic Enzyme

A growing interest exists in documenting the role of paraoxonase 1 (PON1) in different human diseases including, cardiovascular disease, obesity, diabetes mellitus, cancers, aging, and several neurological disorders. Three aspects of PON1 have attracted the attention of researchers: (1) hydrolyzing and detoxifying of toxic organophosphorous compounds such as nerve gases; (2) antioxidative activity in hydrolyzing oxidized phospholipids in high-density lipoprotein (HDL) and low-density lipoprotein (LDL); (3) interaction with various drugs. Drugs and nutrients which can increase the activity of paraoxonases contribute to reduce atherosclerosis and other disorders. There were contradictory reports on the interactions of PON1 with various drugs. These findings may be a reflection of differences in the dosage and type of drug, length of treatment, genetic variations, particularly loss-of-function polymorphisms, and the model used (cultured cells, animal studies or human studies). In addition, it should be noted that the regulatory effects of a drug on the enzyme protein may be important because a drug may induce the PON1 gene while having inhibitory effects on its enzymatic activity. Due to the association of PON1 with various human diseases, this review is focused on the pharmacological aspects of PON1 and the study of interactions between the enzyme and various drugs that may potentially assist to better understand the role of PON1 in drug metabolism, as well as the effects of drugs on PON1 status (activity and gene expression). In general, increasing our knowledge about the antioxidant and antiatherogenic enzyme will assist in determining efficient preventive and therapeutic strategies in the management of human disorders, particularly vascular diseases and those which are associated with negative regulation of PON1.

Paraoxonase 1 (PON1) Q192R genotypes and their interaction with smoking strongly increase atherogenicity and the Framingham risk score.

Paraoxonase 1 (PON1) polymorphisms are associated with an increased susceptibility to cardiovascular disease. PON1 Q192R polymorphism (rs662) partially determine PON1 hydrolytic activity and protect against oxidation of LDL and HDL. This study aimed to delineate the association of PON1 status (functional 192 genotype and plasma activity levels) and atherogenicity in urbans residents aged 40 years or more. Anthropometric data, lipid profiles, the atherogenic index of the plasma (AIP) and Framingham score risk were measured. Three kinetic assays were conducted to assay PON1 status using phenylacetate and 4-(chloromethyl)phenyl acetate as substrates. Smoking per se did not significantly impact the AIP but the interaction PON1 genotype by smoking significantly increased the AIP. In subjects with the RR genotype smoking increased the AIP index from (estimated mean ± SEM) -0.038 ± 0.039 to 0.224 ± 0.094. The QR genotype increased the Framingham risk index by around 1.3 points. Smoking by RR genotype carriers significantly increased the Framingham risk score (17.23 ± 2.04) as compared to smoking (13.00 ± 1.06) and non-smoking (7.79 ± 0.70) by QQ+QR genotype carriers. The interaction RR genotype by smoking was a more important predictor (odds ratio = 7.90) of an increased Framingham risk score (> 20) than smoking per se (odds ratio = 2.73). The interaction smoking by RR genotype carriers significantly increased triglycerides and lowered HDL cholesterol. Smoking per se has no (AIP) or a mild (Framingham risk score) effect on atherogenicity, while the interaction smoking by PON1 RR genotype has a clinically highly significant impact on atherogenicity.

Preliminary study on serum paraoxonase-1 status and chemokine (C-C motif) ligand 2 in hospitalized elderly patients with catheter-associated asymptomatic bacteriuria.

Urinary tract infections (UTI) are common among elderly patients in residential care facilities, as well as in the hospital setting. Identifying new biochemical markers of UTI is an active line of research since UTI management is resource intensive. Paraoxonase-1 (PON1) forms part of the patient's immune system, the response-to-injury and inflammation. Our study sought to evaluate alterations in inflammation-related paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2) in patients with an indwelling catheter to assess their potential usefulness as biomarkers of infection. Patients (n = 142) who had had the urinary catheter removed and 100 healthy volunteers were recruited. In all participants we measured serum PON1 activity, PON1 concentration, CCL2, procalcitonin and C-reactive protein (CRP). Results indicated that patients had higher CCL2, CRP and procalcitonin concentrations than the control group, and lower paraoxonase activity. There were no significant differences in PON1 concentrations. When comparing the diagnostic accuracy of CRP, procalcitonin, CCL2 and the PON1-related variables in discriminating between patients with and those without UTI, we found a considerable degree of overlap between groups, i.e., a low diagnostic accuracy. However, there were significant inverse logarithmic correlations between serum paraoxonase activity and the number of days the urinary catheter had been in situ. Our results suggest that measurement of these biochemical variables may be useful in investigating complications of long-term use of these devices and help to improve the economic and clinical investment required in the management of the often-associated infection.