Lower Serum Paraoxonase-1 Activity Research Articles

CAMEL MILK MODULATES LIPID METABOLISM, EXPRESSION OF ENZYMATIC ANTIOXIDANTS GENES AND PARAOXONASE ACTIVITY IN RATS FED HIGH CHOLESTEROL DIET

Current findings aimed to find out camel milk's effects on lipid metabolism, expression of the genes for antioxidant enzymes and paraoxonase-1 (PON-1) activity in rats fed diet-containing cholesterol 1%. Therefore, 30 rats were divided into three groups (10 rats per each). Rats of the first group, which acted as a control group, fed a basic diet. Rats of the second group fed a basal diet that included 1% cholesterol however, rats of the third group fed cholesterol 1% accompanied by oral administration of camel's milk (100mL/24h/cage/5 rats) as the only source of water for them. Diet of cholesterol 1% induced significant increase in serum total cholesterol, triacylglycerol (TAG), low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities whereas lower serum PON-1 activity was observed when compared to control. Diet of cholesterol 1% induced significant increase in hepatic Thiobarbituric acid reactive substance (TBARS) however, compared to the control, a significant decrease in the activity and gene expression of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione-S transferase (GST), and reduced glutathione (GSH) were detected. These detrimental effects were ameliorated into accepted range in camel milk treated group. Fatty degeneration and fatty cysts in liver tissues were detected in rats fed cholesterol diet but the affected liver showed acceptable degree of recovery in camel milk treated group. Conclusively, camel milk was potential for the treatment of hyperlipidemia and hypercholesterolemia in rats.

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.

Evaluating the link between Paraoxonase-1 levels and Alzheimer's disease development.

At present, the etiopathogenesis of Alzheimer's disease (AD), the most common form of dementia, remains far to be fully deciphered. In the recent years, also the centrality of amyloid-β peptide in the pathogenesis of the neurodegenerative disease has been questioned and other hypotheses have been advanced. Notably, a common denominator of many of these theoretical models is represented by oxidative stress, which is widely proposed to play a role in the disease initiation and/or progression. Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that endows its carrier with multiple biological functions, including the ability to contrast oxidative damage to lipid components of lipoproteins and cells and protect from toxicity of specific organophosphorus pesticides. The peculiar multi-functionality nature of PON1 might be the key for explaining the vast epidemiological data showing a close association between low serum PON1 activity and risk of several diseases, including cardiovascular and neurodegenerative diseases, in particular AD. In this review, we discuss the possible link between PON1 with AD pathogenesis and we hypothesize eventual mechanistic pathways that could account from epidemiological observations. We also highlight the methodological issue limitation in PON1 studies that still impede to give a definitive and certain picture of its effective biological impact on human health including AD.

Effect of continuous renal-replacement therapy on paraoxonase-1-related variables in patients with acute renal failure caused by septic shock

BackgroundAcute renal failure in patients with sepsis is associated with high mortality. Studies have highlighted alterations in serum paraoxonase-1 in severe infections. However, the published literature has no insight into the clinical evolution of these parameters in patients with sepsis and acute renal failure treated with extra-renal depuration techniques. MethodsWe studied 25 patients with sepsis and acute renal failure who were treated with continuous renal-replacement therapy. Blood for laboratory analyses was collected at days 0, 1, 2, 5, 7, and 10. We measured serum paraoxonase-1 activity and concentration, lipid profile, aminotransferase activities, pH, and lactate, urea, creatinine and C-reactive protein concentrations. Values were compared with those of 50 healthy individuals. ResultsPatients with sepsis and acute renal failure had lower serum paraoxonase-1 activity, lower high-density lipoprotein cholesterol concentrations, and higher serum paraoxonase-1 concentrations than the control group. We found a significant inverse correlation between serum paraoxonase-1 concentrations and the Acute Physiology And Chronic Health Evaluation II score in survivors as well as non-survivors, and a significant inverse correlation between serum paraoxonase-1 concentrations and the Sequential Organ Failure Assessment score only in survivors. Extra-renal depuration techniques produced a further increase in this enzyme related to the duration of treatment, and to serum urea concentration. ConclusionOur results show an inverse relationship between the concentration of paraoxonase-1 and the disease severity of patients with renal failure caused by septic shock. These results highlight relationships between paraoxonase-1 and infectious diseases and sepsis, with insights into potential clinical evolution of treatment.

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population.

BACKGROUNDFamilial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients.OBJECTIVETo investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients.DESIGNCase-control study.SETTINGTertiary care center, Riyadh.METHODSTwo hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis.MAIN OUTCOME MEASUREThe strength of association between the Q192R polymorphism and FH in the Saudi population.RESULTSWe confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05–3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13–3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09–2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population.CONCLUSIONIn conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH.LIMITATIONOnly a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

How HDL protects LDL against atherogenic modification: paraoxonase 1 and other dramatis personae.

To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL. Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties. The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates.

Effects of smoking on serum paraoxonase 1 activity and carotid atherosclerosis

Objective To explore the effects of smoking on serum paraoxonase1( PON1) activity and carotid atherosclerosis. Methods 478 subjects from residents of health screening for cardiovascular disease were enrolled from June 2012 to July 2014 in Huangpu district, shanghai. Smoking, drinking, exercise and cardiovascular disease risk factor data were recorded and gathered. All subjects accepted carotid artery ultrasound examination and were measured serum PON1 activity. The lowest quartile of serum PON1 activity level was taken as low PON1 activity level. Results (1) Serum PON1 activity in smokers was lower than that in non-smokers((206.5±25.6)kU/L vs (230.9±38.1)kU/L, P<0.01), incidence of carotid artery atherosclerosis in smoking group was higher than non-smoking group(75.7% vs 56.1%, P<0.01). (2) Multivariate logistic regression analyses indicated smoking, lack of exercise, creatinine, LDL-C were the independence factors of PON1 activity. (3) Multivariate logistic regression analyses indicated smoking, serum PON1 activity, age, gender, systolic pressure, were the independence factors of carotid atherosclerosis. Conclusion Smoking reduces serum activity. Smoking and lower serum PON1 activity level are independent risk factors of carotid atherosclerosis. Key words: Smoking; Paraoxonase 1; Carotid atherosclerosis; Risk factors

Lower Serum Paraoxonase-1 Activity Is Related to Linoleic and Docosahexanoic Fatty Acids in Type 2 Diabetic Patients

Serum paraoxonase-1(PON-1) activity is decreased in clinical conditions associated with low high-density lipoprotein cholesterol (HDL-C), increased lipid peroxidation and low-grade chronic inflammation, as in type 2 diabetes mellitus (T2DM). Until now there are no data about the association of any fatty acid (FA) with PON-1 activity in T2DM. Twenty patients with T2DM and 16 healthy controls were included in this cross-sectional study. Serum PON-1 activity, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity as well as plasma glucose, HbA1c, lipids, high-sensitivity C-reactive protein (hs-CRP) and insulin resistance, homeostasis model assessment (HOMA-IR) were measured. The preparation of FA methyl esters and their gas chromatography (GC) analysis were also performed. HbA1c, plasma insulin, HOMA-IR and triglycerides were higher in patients with T2DM, whereas HDL-C was lower in those subjects. Levels of pro-oxidative enzyme malondialdehyde (MDA) and hs-CRP were significantly higher, and anti-oxidative enzymes SOD and PON-1 activity were decreased in T2DM patients. N-6 PUFAs were higher in T2DM patients, particularly linoleic acid (LA, 18:2 n-6) and arachidonic acid (AA, 20:4 n-6), whereas n-3 PUFA, docosahexaenoic acid (DHA, 22:6 n-3) was lower in T2DM patients. Using regression analysis, we have shown that only LA and DHA independently predicted PON-1 activity of all participants, particularly in patients with T2DM. Decreased serum PON-1 activity may, in part, be influenced by higher levels of LA and lower levels of DHA in patients with T2DM. Prospective, randomized studies are necessary to confirm these preliminary findings.

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.

Serum paraoxonase 1 activity and oxidant/antioxidant status in Saudi women with polycystic ovary syndrome

Oxidative stress is considered to be implicated in the pathophysiology of polycystic ovary syndrome (PCOS). This study was designed to evaluate the paraoxonase 1 (PON1) activity and oxidant/antioxidant status in Saudi women with PCOS and its contribution to the risk of atherosclerosis. Lipid profile, hormonal parameters, serum PON1 activity and oxidant (malondialdehyde)/antioxidant (total antioxidant capacity (TAC) levels were analyzed in 35 patients with PCOS and 30 healthy controls using a spectrophotometric method; correlation analysis was made between these variables. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Women with PCOS had significantly higher fasting insulin, HOMA-IR and LH levels than controls. Lipid profiles and free androgen index (FAI) were significantly higher in women with PCOS when compared with controls. Serum PON1 activity was lower in the PCOS group (161.2 ± 6.1 U/l vs. 217.6 ± 9.3 U/l, p < 0.001) compared with controls, whereas malondialdehyde levels were higher in the PCOS group (4.26 ± 0.18 nmol/ml vs. 1.37 ± 0.12 nmol/ml, p < 0.001) compared with controls. Total antioxidant capacity was lower in the PCOS group (0.88 ± 0.10 mmol Trolox/l vs. 1.63 ± 0.17 mmol Trolox/l, p < 0.001) compared with controls. In PCOS group, serum PON1 was positively correlated with HDL-C ( r = 0.425, p < 0.05) and TAC ( r = 0.582, p < 0.01) but inversely correlated with HOMA-R ( r = −0.54, p < 0.01), testosterone ( r = −0.672, p < 0.01), FAI ( r = −0.546, p < 0.01) and malondialdehyde ( r = −0.610, p < 0.01). In conclusion, our data indicate that PON1 activity and antioxidant status were significantly decreased in Saudi women with PCOS. Lower serum PON1 activity might contribute to the increased susceptibility for the development of atherosclerosis risk in Saudi women with PCOS. Therefore, measurement of serum PON1 activity may be of value in assessment of women at higher risk for development of atherosclerosis risk in PCOS. However, further studies with larger sample size are needed to verify these results, and to assess the efficacy of antioxidant therapy on these patients.

Risk of carotid atherosclerosis is associated with low serum paraoxonase (PON1) activity among arsenic exposed residents in Southwestern Taiwan

To understand whether human paraoxonase 1 (PON1) would modulate the risk for arsenic-related atherosclerosis, we studied 196 residents from an arseniasis-endemic area in Southwestern Taiwan and 291 age- and sex-matched residents from a nearby control area where arsenic exposure was found low. Carotid atherosclerosis was defined by a carotid artery intima-media wall thickness (IMT) of > 1.0 mm. Prevalence of carotid atherosclerosis was increased in the arseniasis-endemic area as compared to the control area after adjustment for conventional risk factors (OR = 2.20, p < 0.01). The prevalence was positively associated with cumulative arsenic exposure (mg/L-year) in a dose-dependent manner. Multiple logistic regression analysis showed that in the endemic group, low serum PON1 activity was an independent risk factor for atherosclerosis (OR = 4.18 low vs. high, p < 0.05). For those of low PON1 activity and high cumulative arsenic exposure, the odds ratio for the prevalence of atherosclerosis was further increased up to 5.68 ( p < 0.05). No significant association was found between atherosclerosis and four polymorphisms of the PON gene cluster (PON1 − 108C/T, PON1 Q192R, PON2 A148G, PON2 C311S). However, genetic frequencies of certain alleles including PON1 Q192, PON2 G148 and PON2 C311 were found increased in the endemic group as compared to the controls and a general Chinese population, indicating a possible survival selection in the endemic group after a long arsenic exposure history. Our results showed a significant joint effect between arsenic exposure and serum PON1 activity on carotid atherosclerosis, suggesting that subjects of low PON1 activity may be more susceptible to arsenic-related cardiovascular disease.

Assessment of paraoxonase activities in patients with knee osteoarthritis

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

Paraoxonase-1 activity in patients with hyperemesis gravidarum

There is increasing evidence that oxidative stress may play a role in the pathophysiology of hyperemesis gravidarum. Serum paraoxonase-1 (PON-1) is a high density lipoprotein (HDL)-associated enzyme that prevents oxidative modification of low density lipoprotein. The aim of the study was to measure the serum levels of PON-1 activity in women with hyperemesis gravidarum. Thirty-four women with hyperemesis gravidarum and 31 healthy pregnant women were enrolled in the study. Serum PON-1 activity was measured spectrophotometrically. Lipid hydroperoxide (LOOH) levels were measured by iodometric assay. PON-1 activity was significantly lower and LOOH levels were significantly higher in pregnant women with hyperemesis gravidarum than in healthy pregnant women (P < 0.0001, for all). There were significant correlations between PON-1 and LOOH, triglyceride, total cholesterol, HDL, low density lipoprotein (LDL) and high sensitive C-reactive protein (HSCRP; P < 0.0001, for all). By using multiple regression analysis LDL, HDL, HSCRP and LOOH were independent determinants of serum PON-1 activity in the study. Decreased PON-1 activity might be related to increased oxidative stress and inflammation in pregnant women with hyperemesis gravidarum. Subjects with hyperemesis gravidarum might be more prone to the development of atherogenesis due to low serum PON-1 activity.

Oxidative status and serum PON1 activity in beta-thalassemia minor

Objectives: Paraoxonase-1 (PON1) deficiency is related to increased susceptibility to low density lipoprotein oxidation and development of atherosclerosis. The aim of this study was to investigate paraoxonase and arylesterase activities along with oxidative status parameters, and to find out if there is any increased susceptibility to atherogenesis, which might be reflected with increased oxidative stress and decreased serum PON1 activity in beta-thalassemia minor (BTM) subjects. Design and methods: Thirty-two subjects with BTM and 28 healthy subjects as control were enrolled in the study. Serum paraoxonase and arylesterase activities, lipid hydroperoxide (LOOH) levels, total antioxidant capacity (TAC), total oxidant status (TOS) and oxidative stress index (OSI) were determined. Results: Serum TAC, paraoxonase and arylesterase activities were significantly lower in BTM subjects than controls (for all p < 0.001), while TOS, LOOH levels and OSI were significantly higher ( p < 0.001, p < 0.05 and p < 0.001; respectively). In BTM subjects, OSI, TOS, LOOH levels and TAC were significantly correlated with serum paraoxonase ( r = − 0.245, p < 0.05; r = − 0.231, p < 0.05; r = − 0.264, p < 0.05 and, r = 0.342, p < 0.05, respectively) and arylesterase activities ( r = − 0.332, p < 0.05, r = − 0.308, p < 0.05; r = − 0.320, p < 0.05 and r = 0.443, p < 0.05). Additionally, hemoglobin level was also correlated with serum paraoxonase ( r = 0.501, p < 0.001) and arylesterase activities ( r = 0.501, p < 0.001), TAC ( r = 0.402, p < 0.05), TOS ( r = − 0.274, p < 0.05) and OSI ( r = − 0.352, p < 0.05). Conclusions: Oxidative stress is increased, while serum PON1 activity is decreased in BTM subjects. Decrease in PON1 activity seems to be associated with both the degree of oxidative stress and anemia. BTM subjects may be more prone to development of atherogenesis due to low serum PON1 activity.

Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy

Sporadic amyotrophic lateral sclerosis (sALS) is a devastating neurodegenerative disease, which results from complex genetic and environmental interactions. Recent studies have reported an association between several polymorphisms of the PON1 and PON2 genes and risk of sALS. The aim of the present study was to identify an association between the – A162G polymorphism of the promoter region of the human PON1 gene and the risk of sALS in a Polish population.We included 259 patients with a diagnosis of definite or probable sALS (76 bulbar onset, 183 limb onset) and 694 healthy controls matched for age and sex. The diagnosis of ALS was established according to El Escorial criteria. The polymorphism was studied by Single Nucleotide Polymorphism Real-Time Polymerase Chain Reaction analysis.No overall difference in the PONI – A162G genotype and allele distribution was seen between cases and controls (all p > 0.05). There was, however, a difference in the A allele frequency when the bulbar onset group was compared to the controls (p = 0.03), but this significance disappeared after the Bonferroni correction.The results did not show that the – A162G polymorphism of the PON1 gene is a risk factor of sALS in a Polish population; it may affect, however, bulbar onset of the disease.Sporadyczna postać stwardnienia bocznego zanikowego (sSLA) jest chorobą zwyrodnieniową układu nerwowego, w której etiopatogenezie kluczową rolę odgrywają interakcje między czynnikami genetycznymi i środowiskowymi. Dotychczasowe badania wskazują na istnienie zależności między polimorfizmami genów PON1 i PON2 a ryzykiem wystąpienia sSLA. Celem pracy było zbadanie, czy istnieje związek między polimorfizmem – A162G miejsca promotorowego genu PON1 a ryzykiem wystąpienia sSLA w populacji polskiej.Badanie przeprowadzono u 259 chorych, uktórych zgodnie z kryteriami El Escorial rozpoznano pewne lub prawdopodobne SLA (76 osób z postacią opuszkową, 183 osoby z postacią kończynową) oraz u 694 zdrowych ochotników, stanowiących grupę kontrolną dobraną pod względem wieku i płci. Polimorfizm genu PON1 był badany za pomocą reakcji łańcuchowej polimerazy DNA z analizą ilości produktu w czasie rzeczywistym.Nie stwierdzono istotnych statystycznie różnic w rozkładzie genotypów i alleli genu PON1 między grupą chorych a grupą kontrolną (p > 0,05). Stwierdzono natomiast różnice w częstości występowania allela A między grupą chorych z postacią opuszkową w porównaniu z grupą kontrolną (p = 0,03), jednak po korekcie Bonferroniego wynik ten nie był już istotny statystycznie.Wyniki naszego badania nie wykazały, aby polimorfizm – A162G genu PON1 był czynnikiem ryzyka sSLA w populacji polskiej, jednak sugerują, że może mieć znaczenie dla wystąpienia postaci opuszkowej tej choroby.

Paraoxonase and atherosclerosis.

There is considerable evidence that the antioxidant activity of high density lipoprotein (HDL) is largely due to the paraoxonase-1 (PON1) located on it. Experiments with transgenic PON1 knockout mice indicate the potential for PON1 to protect against atherogenesis. This protective effect of HDL against low density lipoprotein (LDL) lipid peroxidation is maintained longer than is the protective effect of antioxidant vitamins and could thus be more important. There is evidence that the genetic polymorphisms of PON1 least able to protect LDL against lipid peroxidation are overrepresented in coronary heart disease, particularly in association with diabetes. However, these polymorphisms explain only part of the variation in serum PON1 activity; thus, a more critical test of the hypothesis is likely to be whether low serum PON1 activity is associated with coronary heart disease. Preliminary case-control evidence suggests that this is indeed the case and, thus, that the quest for dietary and pharmacological means of modifying serum PON1 activity may allow the oxidant model of atherosclerosis to be tested in clinical trials.

Low paraoxonase activity in type II diabetes mellitus complicated by retinopathy

Human serum paraoxonase 1 (PON1) is located on high-density lipoprotein and has been implicated in the detoxification of organophosphates, and possibly in the prevention of lipid peroxidation of low-density lipoprotein. PON1 has two genetic polymorphisms, both due to amino acid substitutions: one involving glutamine (Q genotype) and arginine (R genotype) at position 192, and the other involving leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effects of these polymorphisms, and of a polymorphism of the PON2 gene at position 310 (Cys/Ser; C and S genotypes respectively), on serum PON1 activity and concentration, plasma lipids and lipoproteins and glycaemic control in 93 individuals with type II diabetes with no complications and in 101 individuals with type II diabetes with retinopathy. Serum PON1 activity in the group with no complications [median 164.1 nmol.min(-1).ml(-1) (range 8.0-467.8)] was significantly higher than in the group with retinopathy [113.4 nmol. min(-1).ml(-1) (3.0-414.6)] (P<0.001), but the serum PON1 concentration was not different between the groups. The gene frequencies of the PON1-55 and PON1-192 polymorphisms and of the PON2-310 polymorphism were not different between the study populations. The PON1-55 and PON1-192 polymorphisms affected PON1 activity in the way described in a previous study of a control group and subjects with type II diabetes. The PON2-310 polymorphism also significantly affected serum PON1. PON1 activity was significantly higher in individuals with the PON2-310 CC genotype in both groups with type II diabetes, and the PON1 concentration was significantly higher in PON2-310 CC homozygotes with no complications than in the group with retinopathy. Neither the PON1-55 nor the PON1-192 polymorphism was correlated with the serum lipid or lipoprotein concentration in either group. In the group with retinopathy (but not the group with no complications), all three PON polymorphisms were correlated with glycaemic control, which was worse for the PON1-55 genotypes in the order MM>LM>LL (P=0.0032), for the PON1-192 genotypes in the order RR>QR>QQ (P=0.011) and for the PON2-310 genotypes in the order CC>CS>SS (P=0.010). Low serum PON1 activity in retinopathy may be related to an increased tendency for lipid peroxidation. Our findings thus raise the possibility that, in retinopathy, the PON2 gene may influence PON1, and that an inter-relationship between the PON1 and PON2 genes may influence glycaemic control in subjects with type II diabetes complicated by retinopathy.