Disease relevance of PON1

• Decreased coronary heart disease (CHD) risk associated with polymorphisms of PON1 which are most active in lipid peroxide hydrolysis revealed by meta-analysis is likely to be an underestimate of the true contribution of PON1 to CHD because these polymorphisms explain only a small component of the variation in PON1 activity [1].
• Experiments with transgenic PON1 knock-out mice indicate the potential for PON1 to protect against atherogenesis [1].
• Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, although the genotype at four functional PON1 polymorphisms is not [2].
• PON1 is atheroprotective in animal models of hypercholesterolemia [3].
• We evaluated whether susceptibility to noise-induced hearing loss (NIHL) is associated with SOD2, PON1, and PON2 polymorphisms in workers exposed to prolonged loud noise [4].

Psychiatry related information on PON1

• The paraoxonase (PON1) Gln192-->Arg polymorphism was examined in a group of sporadic late-onset Alzheimer's disease (AD) patients, in a group of coronary artery disease (CAD) patients, and in normal subjects [5].
• The areas of atherosclerotic lesions in LAD appear to be dependent on the amount of alcohol consumption, especially in men carrying the PON1 M55 allele [6].
• We studied the effect of dietary modifications on PON1 activity and the role of PON1 gene polymorphisms in the response [7].
• We have previously shown that serum PON1 activity (PON1a) is lower in vascular dementia (VaD) than in Alzheimer's disease (AD), suggesting that PON1a may distinguish VaD from AD [8].
• Individual differences in detoxication capacities for specific organophosphorous (OP) compounds are due largely to differences in catalytic efficiency or abundance of the HDL-associated enzyme, paraoxonase (PON1) [9].

High impact information on PON1

• We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OP, extending earlier studies on this system [10].
• We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective [10].
• Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values [10].
• The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors by cytochrome P-450 systems [10].
• A genetic polymorphism of paraoxonase (PON) activity which determines high versus low paraoxon hydrolysis in human populations, may determine sensitivity to parathion poisoning [11].

Chemical compound and disease context of PON1

• Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism [12].
• RESULTS: A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke (P=0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates) [13].
• Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls [14].
• Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance [14].
• The activity of PON1 is affected by the methionine for leucine substitution at position 55 (M55L) and increased during regular moderate alcohol consumption, consistent with increased HDL cholesterol concentration [6].

Biological context of PON1

• However, among white women, when data were stratified by the number of diseased vessels, the frequency of the PON1 codon 192 Arg/Arg genotype was significantly higher in the group with three-vessel disease than in the other groups (those with one-vessel and two-vessel disease) combined (17.02% vs. 4.58%; P=.0066) [15].
• We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD [16].
• PON1 activity and mass are both reduced in cardiovascular diseases and the hypocholesterolemic drugs, statins, increase serum PON1 activity (by reducing oxidative stress, or by upregulating hepatic PON1 expression) [17].
• In contrast, a serine esterase inhibitor abolished phospholipase activity even though PON1 has no active-site serine residues [18].
• With regard to the PON1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied [19].

Anatomical context of PON1

• PON1 protects lipids in lipoproteins, in macrophages and in erythrocytes from oxidation [17].
• Beyond its antioxidative properties, PON1 possesses additional antiatherogenic properties against macrophage foam cell formation: attenuation of cholesterol and oxidized lipids influx, inhibition of macrophage cholesterol biosynthesis and stimulation of macrophage cholesterol efflux [17].
• Paraoxonase (PON1) is a serum esterase exclusively associated with high-density lipoproteins; it might confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids in oxidized low-density lipoproteins [20].
• To address this inconsistency, we investigated the role of all common PON1 genetic variability, as measured by tagging single-nucleotide polymorphisms (tagSNPs), in predicting PON1 activity for phenylacetate hydrolysis, LDL susceptibility to oxidation ex vivo, plasma homocysteine (Hcy) levels, and carotid artery disease (CAAD) status [2].
• PON1 activity was strongly dependent upon the promoter alleles in both maternal and cord blood [21].

Associations of PON1 with chemical compounds

• The adjusted odds ratios for the development of three-vessel disease were 2.80 (95% confidence interval 1.06-7.37; P=.038) for PON1 codon 192 Arg/Arg and 3.68 (95% confidence interval 1.26-10.68; P=.017) for PON2 codon 311 Cys/Cys [15].
• PON1 requires divalent cations, but EDTA did not block the phospholipase A(2) activity of PON1 [18].
• We conclude that, upon HDL oxidation with peroxynitrite, apolipoprotein AI increases the formation of phosphatidylcholine core aldehydes that are subsequently hydrolyzed by PON1 [22].
• The PON1 gene is regulated by Sp1 and protein kinase C, whereas the PON2 gene in macrophages is regulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [17].
• Neither PON1 activity nor PON1 genotype was significantly correlated with plasma Hcy levels [2].

Physical interactions of PON1

• LCAT has been reported to be involved in reverse-cholesterol transport and PON to be preventive for lipid peroxidation of low-density lipoprotein in vitro [23].
• Paraoxonase (PON) is transported primarily on apolipoprotein A-I (apoA-I) -containing high-density lipoprotein (HDL) and is thought to protect against early atherogenic events including low-density lipoprotein (LDL) oxidation and monocyte migration [24].

Regulatory relationships of PON1

• Apolipoprotein A-I promotes the formation of phosphatidylcholine core aldehydes that are hydrolyzed by paraoxonase (PON-1) during high density lipoprotein oxidation with a peroxynitrite donor [22].
• The PON1 promoter polymorphism C(-108)T may influence insulin sensitivity by modulating serum antioxidant capacity [25].
• NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP [26].
• Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01) [27].
• PON1 attenuates the ox-LDL induced MCP-1 production by endothelial cells [28].

Other interactions of PON1

• Three polymorphisms in the PON1 (Leu55Met and Gln192Arg) and PON2 (Ser311Cys) genes have been shown to be associated with the risk of CAD in several European or European-derived populations [15].
• Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization [29].
• However, the effect of apolipoprotein A-I and paraoxonase-1 (PON-1) on phosphatidylcholine oxidation products has not been identified [22].
• METHODS: Polymorphisms of three xenobiotic genes (CYP17, GSTP1, PON1) were characterized in 384 patients with untreated PCa and 360 age-matched control patients with benign prostatic hyperplasia (BPH) [30].
• The odds ratios (OR) adjusted for age, gender, and APOE polymorphism by logistic regression analysis highlighted that in AD the PON1 RR genotype was significantly protective (OR=0.41, 95% CI=0.19-0.90; P=0.025), whereas in CAD it appeared to be a significant risk factor (OR=5.11, 95% CI=1.09-23.9; P=0.038) limited to younger patients [5].

Analytical, diagnostic and therapeutic context of PON1

• The SOD2 gene was screened by denaturing reversed-phase HPLC, and the PON1 (Q192R and M55L) and PON2 (S311C) polymorphisms were analyzed by PCR amplification followed by digestion with restriction endonucleases [4].
• RESULTS: PON1 activity was highest in the more dense HDL(3) and VHDL fractions where PON1 was not dissociated from the particles during centrifugation [31].
• 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 [32].
• Using site-directed mutagenesis and expression in human 293T cells, we have identified the following eight amino acids as being essential to PON1 activity: W280, H114, H133, H154, H242, H284, E52 and D53 [33].
• Case-control studies of PON1 activity and coronary heart disease (CHD) have shown a clear association between CHD and low serum PON1 activity [34].

References