The Hunt for Nutritional and Pharmacological Modulators of Paraoxonase

Durrington, Paul N.; Mackness, Bharti; Mackness, Mike

doi:10.1161/01.atv.0000027414.34728.1f

Cited by 48 publications

(39 citation statements)

References 49 publications

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“…[33][34][35][36] Our finding that PON1 activity was a stronger prognostic factor in the men at highest risk of a new CHD event, either because they already had clinical evidence of CHD or because other risk factors clustered in them as indicated by the Framingham risk equation, is consistent with several case-control studies in which low PON1 activity or PON1 polymorphisms associated with low activity have been reported to be more prevalent in patients at increased risk by virtue of other risk factors such as age, cigarette smoking, hypertension, hyperlipidemia, and diabetes mellitus. 21,37 It suggests that, were it possible to increase PON1 activity by a nutritional or pharmacological intervention, 37 the adverse effect of some of other risk factors might be ameliorated.…”

Section: Discussionmentioning

confidence: 99%

“…1 The lipid composition of HDL, which is open to nutritional or pharmacological modification, may provide a means of modifying PON1 activity favorably. Furthermore, there may be opportunities to increase the expression of PON1 activity by nutritional or pharmacological effects on its genetic regulation 37 now that promoter polymorphisms of PON1 have been reported to be associated with early onset CHD. 38 Serum clusterin, which is present in the same HDL subspecies as PON1, did not predict new CHD events in this study, nor was it related to the presence of CHD in our previous case-control study.…”

Section: Discussionmentioning

confidence: 99%

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Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study

et al. 2003

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Background-The hypothesis that paraoxonase (PON1) has a role in preventing atherosclerosis is based on experimental, transgenic, and case-control studies but has not previously been tested prospectively. Methods and Results-The Caerphilly Prospective Study is a cohort study of men aged 49 to 65 years observed for coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction) over a mean period of 15 years. Serum PON1 activity toward paraoxon was measured in 1353 participants. PON1 activity was 20% lower in the 163 men who had a coronary event (Pϭ0.039). Men in the highest quintile of PON1 activity had a decreased risk compared with those in the lowest quintile (OR 0.57 [95% CI, 0.33 to 0.96] Key Words: myocardial infarction Ⅲ lipoproteins Ⅲ coronary disease Ⅲ antioxidants P araoxonase (EC.3.1.8.1, aryldialkylphosphatase) (PON1) has been extensively studied in the field of toxicology because it hydrolyses organophosphate compounds, used as insecticides and nerve gases. 1,2 PON1 is synthesized in the liver and in serum is located on HDL. The serum HDL concentration is inversely correlated with atherosclerosis risk. 3 The mechanism for this continues to be the subject of considerable debate. The initial focus of attention was on the role of HDL in reverse-cholesterol transport. However, recent studies have suggested more diverse mechanisms. HDL protects against oxidative modification of LDL, 4 -6 which is believed to be central to the initiation and progression of atherosclerosis. 7 The antioxidant activity of HDL relates to its enzymes, primarily PON1, but also LCAT, 8 and these can prevent lipid-peroxide accumulation on LDL both in vitro and in vivo. 9 -14 PON1 activity is partly genetically determined. An amino acid substitution at position 192 (Q3 R) gives rise to 2 allozymes, 15,16 the relative activities of which are substrate dependent. Substrates, such as paraoxon and fenitroxon, are hydrolyzed faster by the R alloenzyme, whereas other substrates, such as phenyl acetate, are hydrolyzed at the same rate by both alloenzymes, and yet others, such as diazoxon and the nerve gases soman and sarin, are hydrolyzed more rapidly by the Q alloenzyme. 17 The Q alloenzyme in vitro provides greater protection against the accumulation of lipid peroxides on LDL than the R alloenzyme. 18,19 A second exonic polymorphism of the PON1 gene occurs at amino acid position 55 (L3 M). This polymorphism also affects PON1 activity, although less than that of the 192 polymorphism. 20 There have been many case-control studies to test the hypothesis that the 192R allele of the PON1 gene is associated with coronary heart disease (CHD). 21 A recent metaanalysis of these found that the PON1-192R allele was significantly related to the presence of CHD, but there was evidence of publication bias. 22 Furthermore, genetic casecontrol studies fail to test the hypothesis that serum PON1 activity protects against CHD, because the 192 polymorphism accounts for only a small part of the 40-fold individual variation in serum PON1 act...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study

et al. 2003

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“…Research on interactions between genetic and nutritional components is particularly interesting, and attempts are being made to find modulators of serum PON1 activity for therapeutic purposes (9 ). However, because most of the conclusions reported to date have been the result of experimental investigations or intervention studies with patients, it is still unclear how nutritional or other environmental agents affect PON1 activity in the general population.…”

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confidence: 99%

Regulation of Serum Paraoxonase Activity by Genetic, Nutritional, and Lifestyle Factors in the General Population

et al. 2003

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Background: Paraoxonase may protect lipoproteins and cell membranes from peroxidation, and alterations in the activity of this enzyme have been associated with some chronic diseases. Serum paraoxonase appears to be mainly under genetic control, but some studies suggest that environmental factors may also modulate its activity. The aim of the present study was to investigate whether diet and lifestyle affect serum paraoxonase activity. Methods:We studied a population-based sample of 388 individuals (194 women and 194 men; age range, 18 -75 years) and assessed their daily dietary intake using a 3-day estimated food record. The variables studied included serum paraoxonase activity, paraoxonase polymorphisms at positions 55 and 192, age, gender, smoking status, physical exercise, body mass index, energy consumption, nutrient intake (total lipids, saturated fatty acids, ␤-carotenes, vitamins C and E), and serum lipid concentrations. Results: Multiple linear regression analysis showed that only genetic polymorphisms, serum cholesterol, HDL-cholesterol concentrations, and cigarette smoking were significant predictors of serum paraoxonase activity. HDL-cholesterol concentrations were also related to body mass index, daily energy consumption, and saturated fatty acid intake. Conclusions:The between-individual variability of serum paraoxonase activity is regulated mainly by genetic

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“…While preserved PON1 activity has been found in HDL-deficient states (14,33,34), in our patient, PON1 activity was reduced 78% compared with the healthy control subjects (Table III). The interindividual variability in serum PON1 activity seems to be regulated by genetic SNPs, environmental (tobacco, alcohol, fatty acids) (35) and biochemical (HDL-C and total cholesterol levels) (36) factors that may increase or reduce PON1 activity, which may explain the low activity found in the proband and some of the family members. While ABCA1-mediated cholesterol efflux to total isolated HDL was preserved in mutation carriers (Table III), SRB1-mediated efflux to total isolated HDL was reduced ~50% in the proband relative to the efflux of the healthy control group.…”

Section: Discussionmentioning

confidence: 99%

Premature and severe cardiovascular disease in a Mexican male with markedly low high-density-lipoprotein-cholesterol levels and a mutation in the lecithin:cholesterol acyltransferase gene: A family study

Posadas-Sánchez

Posadas‐Romero

Ocampo-Arcos

et al. 2014

International Journal of Molecular Medicine

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Abstract. Epidemiological and clinical studies have shown that a low plasma high-density lipoprotein cholesterol (HDL-C) level is a strong predictor of cardiovascular disease (CVD). Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the formation, maturation and function of HDL. Therefore impaired LCAT function may enhance atherosclerosis because of defective cholesterol transport. In this study, we examined a 34-year old LCAT-deficient patient and eight first-degree family members. There was a strong family history for CVD and type 2 diabetes mellitus (DM2). The proband was found homozygous for a previously reported LCAT gene mutation (Thr37Met). A sister and two sons of the proband were heterozygous for the same mutation. The proband had DM2 and showed severe multivessel coronary artery disease, corneal opacification and extremely low HDL-C levels. Large HDL particles were absent while small HDL particles were increased. The HDL of the patient had a reduced ability to promote cell cholesterol efflux, and the low-density lipoproteins (LDL) were more susceptible to oxidation. Among his family members, two heterozygotes and one non-carrier had early carotid or coronary atherosclerosis. In conclusion, as the increased LDL oxidability and structural and functional abnormalities of HDL particles have been reported in patients with obesity and diabetes, the results suggested that the adverse coronary risk profile, and not being LCAT deficient, may be responsible for the CVD found in our proband, and for the early atherosclerosis observed in the two heterozygotes and in the wild-type family members.

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The Hunt for Nutritional and Pharmacological Modulators of Paraoxonase

Cited by 48 publications

References 49 publications

Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study

Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study

Regulation of Serum Paraoxonase Activity by Genetic, Nutritional, and Lifestyle Factors in the General Population

Premature and severe cardiovascular disease in a Mexican male with markedly low high-density-lipoprotein-cholesterol levels and a mutation in the lecithin:cholesterol acyltransferase gene: A family study

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