Paraoxonase 1 (PON1) modulates the toxicity of mixed organophosphorus compounds

A transgenic mouse model of the human hPON1_Q192R polymorphism was used to address the role of paraoxonase (PON1) in modulating toxicity associated with exposure to mixtures of organophosphorus (OP) compounds. Chlorpyrifos oxon (CPO), diazoxon (DZO), and paraoxon (PO) are potent inhibitors of carboxylesterases (CaE). We hypothesized that a prior exposure to these OPs would increase sensitivity to malaoxon (MO), a CaE substrate, and the degree of the effect would vary among PON1 genotypes if the OP was a physiologically significant PON1 substrate in vivo. CPO and DZO are detoxified by PON1. For CPO hydrolysis, hPON1_R192 has a higher catalytic efficiency than hPON1_Q192. For DZO hydrolysis, the two alloforms have nearly equal catalytic efficiencies. For PO hydrolysis, the catalytic efficiency of PON1 is too low to be physiologically relevant. When wild-type mice were exposed dermally to CPO, DZO, or PO followed 4-h later by increasing doses of MO, toxicity was increased compared to mice receiving MO alone, presumably due to CaE inhibition. Potentiation of MO toxicity by CPO and DZO was greater in PON1^−/− mice, which have greatly reduced capacity to detoxify CPO or DZO. Potentiation by CPO was more pronounced in hPON1_Q192 mice than in hPON1_R192 mice due to the decreased efficiency of hPON1_Q192 for detoxifying CPO. Potentiation by DZO was similar in hPON1_Q192 and hPON1_R192 mice, which are equally efficient at hydrolyzing DZO. Potentiation by PO was equivalent among all four genotypes. These results indicate that PON1 status can have a major influence on CaE-mediated detoxication of OP compounds.     

Synergistic effect of polymorphisms of paraoxonase gene cluster and arsenic exposure on electrocardiogram abnormality

Arsenic has been linked to increased prevalence of cancer and cardiovascular disease (CVD), but the long-term impact of arsenic exposure remains unclear. Human paraoxonase (PON1) is a high-density lipoprotein-associated antioxidant enzyme which hydrolyzes oxidized lipids and is thought to be protective against atherosclerosis, but evidence remains limited to case-control studies. Only recently have genes encoding enzymes responsible for arsenic metabolism, such as AS3MT and GSTO, been cloned and characterized. This study was designed to evaluate the synergistic interaction of genetic factors and arsenic exposure on electrocardiogram abnormality. A total of 216 residents from three tap water implemented villages of previous arseniasis-hyperendemic regions in Taiwan were prospectively followed for an average of 8 years. For each resident, a 12-lead conventional electrocardiogram (ECG) was recorded and coded by Minnesota Code standard criteria. Eight functional polymorphisms of PON1, PON2, AS3MT, GSTO1, and GSTO2 were examined for genetic susceptibility to ECG abnormality. Among 42 incident cases with ECG deterioration identified among 121 baseline-normal subjects, arsenic exposure was significantly correlated with incidence of ECG abnormality. In addition, polymorphisms in two paraoxonase genes were also found associated with the incidence of ECG abnormality. A haplotype R-C-S constituted by polymorphisms of PON1 Q192R, -108C/T and PON2 C311S was linked to the increased risk. Subjects exposed to high levels of As (cumulative As exposure > 14.7 ppm-year or drinking artesian well water > 21 years) and carrying the R-C-S haplotype had significantly increased risks for ECG abnormality over those with only one risk factor. Results of this study showed a long-term arsenic effect on ECG abnormality and significant gene-gene and gene-environment interactions linked to the incidence of CVD. This finding might have important implications for a novel and potentially useful biomarker of arsenic risk.     

PON1 is a longevity gene: Results of a meta-analysis

Paraoxonase 1 (PON1) is one of the most studied genes regarding cardiovascular risk, oxidative stress and inflammation. Several lines of evidence suggests that PON1 promotes an atheroprotective effect. Patients carrying PON1 codon 192 QQ genotype display a higher risk of cardiovascular events, the major cause of mortality in the elderly: it can be predicted that gene variants increasing the risk of mortality will be under-represented in long-living individuals. We first reported that PON1 R allele (R+) carriers are significantly more represented in Italian centenarians; subsequently this topic has been addressed by many other groups, and here we report a meta-analysis on 11 studies in different populations selected by a review of the literature available in PubMed and testing the effect of the Q192R polymorphism on human ageing. QUORUM guidelines for meta-analysis have been followed, and a total number of 5962 subjects have been included: 2795 young controls (<65 years of age) and 3167 old subjects (>65 years of age). The Mantel-Haenszel weighting for pooling in presence of a fixed effects model has been applied.The meta-analysis of R carriers showed a significant result with an overall OR of 1.16 (1.04–1.30, 95% CI, p = 0.006). The meta-analysis of QR genotype also showed a significant result, with an overall OR of 1.14 (1.02–1.27, 95% CI, p = 0.016).The results show that PON1 gene variants at codon 192 impact on the probability of attaining longevity, and that subjects carrying RR and QR genotypes (R+ carriers) are favoured in reaching extreme ages. These results likely represent the counterpart of the effects observed on cardiovascular diseases (CVD), as centenarians and nonagenarians escaped or delayed the onset of the major age-related diseases, including CVD.     

Relationship between human paraoxonase-1 activity and PON1 polymorphisms in Mexican workers exposed to organophosphate pesticides

Paraoxonase-1 (PON1) is a serum enzyme which catalyzes the hydrolysis of organophosphate pesticides. In this study we conducted a cross-sectional study and reported on the distribution of three common genetic polymorphisms of the PON1 gene in a population of floriculture workers from Mexico as well as the association between those polymorphisms and other predictors with serum PON1 activity on paraoxon, diazoxon and phenylacetate. The genotype frequencies at position PON1₅₅ were 89% (LL), 10% (LM) and 0.6% (MM), at position PON1₁₉₂ they were 16% (QQ), 47% (QR) and 37% (RR), and 26% (TT), 42% (TC) and 32% (CC) at position PON1_−108. Thus, the frequencies of alleles L, Q and T were 0.94, 0.40 and 0.47, respectively. The PON1₅₅ polymorphism had no significant effect on serum PON1 activity on any substrate. We found a significant association between the PON1₁₉₂ polymorphism and PON1 activity towards paraoxon and diazoxon, which increased in genotypes as follows: 192RR > 192QR > 192QQ for paraoxonase activity and, inversely, 192QQ > 192QR > 192RR for diazoxonase activity. The PON1₋₁₀₈ polymorphism also had a significant effect on PON1 activity level towards paraoxon in the following order among the genotype groups: −108CC > −108TC > −108TT. Serum PON1 activity towards diazoxon was not associated with the PON1₋₁₀₈ polymorphism but it was influenced by the intensity exposure to pesticides at the floriculture industry and the years of the occupational exposure to pesticides. No polymorphism significantly influenced serum PON1 activity on phenylacetate.     

中国广东潮汕地区汉族人对氧磷脂酶1(PON1)L55M基因多态性与冠心病伴高血糖的关系

目的观察广东省潮汕地区汉族人群对氧磷脂酶1（PON1）L55M基因多态性与冠心病（CHD）合并空腹血糖升高（FHG）及2型糖尿病（T2DM）的相关关系,及与冠状动脉血管病变数和病变范围的相关关系。方法284例受检者据空腹血糖和冠状动脉造影结果分正常对照组（90例）、CHD组（86例）、CHD＋FHG组（62例）、CHD＋T2DM组（46例）,进行SNPs序列测定入选人群PON1 L55M基因并分析。结果广东地区汉族人群PON1 L55M基因存在多态性,L等位基因频率为0．86。3种基因型（LL,LM,MM）在4组中无明显差异。L等位基因在冠心病病变血管数目和病变范围中无明显差异（Х^2=0．56,P=0．758;Х^2-0．11,P=0．743）。结论中国广东潮汕地区汉族人群中存在PON1 L55M基因多态性,等位基因频率以L型为主。PON1 L55M基因多态性与是否发生空腹血糖升高或糖尿病以及冠状动脉病变严重程度无明显相关性。     

Effects of vitamin C supplementation on oxidative stress and serum paraoxonase/arylesterase activities in patients on long-term hemodialysis

BackgroundOxidative stress increases oxidizability of apolipoprotein-B containing lipoproteins and decreases paraoxonase (PON) activity in hemodialysis (HD) patients and plays an important part in the development of atherosclerotic cardiovascular diseases. In HD patients, plasma ascorbic acid (AA) levels are decreased either due to the loss by hemodialysis membranes or due to malnutrition and contribute to the imbalance of antioxidant defense mechanisms. We hypothesized that long-term ascorbic acid (AA) supplementation recovers oxidizability of lipoproteins in HD patients by reinforcing PON activity.MethodsTwenty-nine adult patients were treated with 100 mg and 500 mg AA at the end of each HD session thrice a week for two consecutive 16 weeks-periods, respectively. Blood samples were obtained before the first HD session and prior to the first HD sessions following the 100 mg AA-supplemented and the 500 mg AA-supplemented periods.ResultsPON activities were significantly increased after 100 mg (p < 0.05) and 500 mg AA (p < 0.001) supplementation periods compared to the basal level. Apo-B lipoprotein oxidizability (Δ-MDA) was significantly decreased after 500 mg AA supplementation compared to both basal (p < 0.05) and 100 mg AA supplementation periods (p < 0.05). Plasma AA concentrations were negatively correlated with Δ-MDA levels (R = −0.327; p < 0.01).ConclusionOur results suggest that long-term parenteral 500 mg AA supplementation improves PON activity alleviating apo B-containing lipoproteins oxidizability in HD patients.     

偏头痛患者对氧磷酶-1活性与氧化低密度脂蛋白水平的变化

目的探讨偏头痛患者血清对氧磷酶-1(PON1)活性和氧化低密度脂蛋白(ox-LDL)水平的变化,揭示偏头痛发病机制与氧化应激的关系。方法将66例偏头痛患者和45名健康体检人群作为研究对象,测定血清中PON1活性和ox-LDL水平。将66例偏头痛患者分成先兆偏头痛患者组(43例)和无先兆偏头痛患者组(23例),比较2组血清中PON1活性和ox-LDL水平的变化。结果偏头痛患者组血清PON1活性低于健康对照组(P<0.01),ox-LDL水平高于健康对照组(P<0.01)。在无先兆偏头痛和先兆偏头痛患者中,PON1活性和ox-LDL水平差异无统计学意义(P>0.05)。血清PON1活性和ox-LDL水平呈负相关(r=-0.523,P<0.01)。结论血清PON1活性和ox-LDL水平变化对于揭示偏头痛的发病机制,预防心脑血管疾病的发生具有重要的意义。     

对氧磷酶与动脉粥样硬化的关系

人血清对氧磷酶 (PON1 )是高密度脂蛋白 (HDL)颗粒中的一种抗氧化酶。近年发现 ,PON1通过参与氧化磷脂的降解抑制低密度脂蛋白 (LDL)氧化 ,是HDL阻止LDL氧化、行使抗动脉粥样硬化功能的关键酶 ,因而倍受关注。大多数研究结果表明 ,PON1浓度和活性与动脉粥样硬化的发生和发展有密切的关系。另外 ,PON1是冠状动脉疾病的遗传标志物 ,通过检测PON1基因多态性 ,可为冠状动脉疾病的预防提供线索     

8-Hydroxydeoxyguanosine levels in human leukocyte and urine according to exposure to organophosphorus pesticides and paraoxonase 1 genotype

Objective In order to investigate a role of paraoxonase 1 (PON1) polymorphism in organophosphorus (OP)-induced 8-hydroxydeoxyguanosine (8-OHdG) levels, urinary metabolites of OP, PON1 genotypes, and 8-OHdG levels in leukocyte and urine were measured in OP indoor insecticide sprayers and controls in summer and winter. Methods The study population contained 18 male sprayers and age-matched 18 male controls. Sprayers were primarily exposed to OP insecticides (mainly fenitrothion, dichlorvos, chlorpyrifos, and diazinon), and partially to pyrethroids (mainly permethrin) and carbamates (mainly propoxur). Urinary metabolites of OP were measured by gas chromatography-mass spectrometry. 8-OHdG levels in leukocyte and urine were measured by ELISA kit. PON1 genotype was identified using allele-specific fluorogenic TaqMan probes. Results The mean concentrations of urinary dimethyl phosphate (DMP) and total dialkyl phosphates (DAP) in summer and those of 8-OHdG in summer and winter were significantly higher in OP sprayers than controls. This resulted in a significant positive correlation between 8-OHdG levels and urinary DMP or DAP, suggesting a correlation between OP metabolites and production of oxidative stress. Of PON1 genotypes, incidences of Q/Q, Q/R, and R/R types were 17, 39, and 44% in OP sprayers and controls, respectively. Although PON1 polymorphism did not contribute to the leukocyte and urinary 8-OHdG levels, the urinary OP metabolite concentrations in summer showed a significant decrease as the number Q allele decreased. Conclusion These results indicate that an increase in OP metabolites is associated with a high level of oxidative stress in OP sprayers, although the contribution of the PON1 polymorphism to the metabolism of OP is still unclear.