ReviewThe three-gene paraoxonase family: Physiologic roles, actions and regulation
Introduction
The paraoxonase (PON) gene family contains three different members (PON1, PON2 and PON3), and exhibits antioxidative properties principally in the blood circulation. Recent interests have been directed towards a better comprehension of the functions of PON2 and PON3, but PON1 remains by far the most studied of the three enzymes.
PON1 is a calcium-dependent esterase that was first described for its capacity to hydrolyze organophosphates and pesticides, including paraoxon, which inspired the name of the three enzymes. PON1 is a 43–45 kDa glycoprotein, expressed in a variety of tissues [1], but it is mainly synthesized by the liver and circulates within high-density lipoprotein (HDL) particles [2]. It has been the focus of more intense research activities, because of its evident capacity to protect low-density lipoproteins (LDL) against oxidative stress, reduce macrophage foam cell formation and prevent atherosclerosis development [3]. PON1 gene polymorphisms have been associated with various human diseases, including coronary heart disease [4], Parkinson's disease [5], type 2 diabetes [6] and inflammatory bowel disease [7].
Despite increasing interest in PON2, there is still little information about its functions and characteristics. Although this member of the PON family does not associate with HDL particles in the circulation, it has also been involved in the reduction of oxidative stress and protection against atherosclerosis [8]. PON2 is expressed in nearly all human tissues, including the lungs, liver, heart and intestine [9]. In vascular cells, PON2 was found to be a cell-based enzyme and appeared in two glycosylated isoforms of approximately 40–43 kDa [10]. PON2 gene polymorphisms have been implicated in a variety of human disorders, such as cardiovascular diseases [11], [12], type 2 diabetes [13], [14] and inflammatory bowel disease [15].
PON3, the third member of the multigene family, is similar to PON1 in terms of expression, function and location. Both recombinant human PON1 and PON3 show the capacity to delay LDL oxidation in vitro, with PON1 being more effective than PON3 in this respect [16]. Few data are available for the moment on PON3 polymorphisms and the effects of these variants on human diseases are still unknown [17].
All three PONs seem to be important players in the maintenance of a low oxidative state in the blood circulation and, therefore, the prevention of atherosclerosis. Associations of their polymorphisms with various human diseases show a potential implication of these enzymes in other organs. Of note, PON1 gene polymorphisms have been shown to account for more than 60% of the interindividual variation in enzyme concentration and activity but the three PONs have shown to be modulated by various nutritional and pharmacological molecules and some pathophysiological events such as inflammation and oxidative stress. The purpose of this review is to summarize and update of the major functions attributed to PONs, as well as the nutritional, physiological and pharmacological influences of PON expression and activity in relation to disease. Identifying lifestyle modifications that favor PON expression and activity could have a major impact on atherosclerosis and many other oxidative stress-related diseases. In addition, the discovery of pharmacological products that modulate PONs could be of major clinical importance.
Section snippets
Physiological roles of PON1
PON1 was first studied for its capacity to detoxify organophosphate compounds [18], but the current paper will focus primarily on its antioxidative and anti-inflammatory properties as well as on the potential pathophysiological implications of its modulation.
HDLs are the most powerful independent negative predictors of cardiovascular events. The protective effects of HDLs have first been attributed to their capacity to promote cellular cholesterol efflux from peripheral cells and deliver it to
Physiological roles of PON2
Less information is available regarding the specific functions and regulation of PON2. However, like PON1, it has been implicated in oxidative stress, inflammation and quorum-sensing regulation. Its antioxidative properties may be related to atherosclerosis prevention, although PON2 protein is not detectable in HDL particles. However, PON2 is expressed in nearly all human tissues with a primary localization in the plasma membrane, which suggests functions that are distinct from those reported
Physiological roles of PON3
The biological functions of PON3 were clarified with the pioneer work of Draganov et al. in 2000 [181]. Characterization of rabbit PON3 was carried out following its purification and it interestingly co-purified with PON1 and apo A-I, both known components of HDL, indicating the location of PON3 within HDL particles. Substrate specificity was found to be quite different, as PON3 had no paraoxonase activity and very limited arylesterase activity, but was endowed with a much greater lactonase
Conclusions
PONs (1, 2 and 3) are still relatively newly identified antioxidant enzymes and much more work needs to be done in order to fully elucidate their physiological functions as well as understand their modulation and their implications for human health. PON1, 2 and 3 can all prevent atherosclerosis and control oxidative stress in the blood circulation. Oxidised lipids have shown to be potential substrates for PONs, which could explain their beneficial implication in oxidative stress and
Acknowledgments
This study was supported by the Crohn's and Colitis Foundation of Canada, the JA deSève Research Chair in Nutrition (EL) and the Fonds de la Recherche en Santé du Québec (LPP). The authors thank Mrs Schohraya Spahis for her technical assistance.
References (189)
- et al.
Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues
Free Radic Biol Med
(2008) - et al.
Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development
Free Radic Biol Med
(2004) - et al.
Association between PON 1 polymorphisms, PON activity and diabetes complications
J Diabetes Complications
(2006) - et al.
Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein
J Biol Chem
(2001) - et al.
PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients
Atherosclerosis
(2001) - et al.
Comparison of the ability of paraoxonases 1 and 3 to attenuate the in vitro oxidation of low-density lipoprotein and reduce macrophage oxidative stress
Free Radic Biol Med
(2008) - et al.
Identification of paraoxonase 3 gene (PON3) missense mutations in a population of southern Italy
Mutat Res
(2004) - et al.
Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein
FEBS Lett
(1991) - et al.
Paraoxonase-1 deficiency in mice predisposes to vascular inflammation, oxidative stress, and thrombogenicity in the absence of hyperlipidemia
Cardiovasc Pathol
(2008) - et al.
Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities
J Lipid Res
(2005)
Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation
J Biol Chem
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
J Biol Chem
Multiple substrates for paraoxonase-1 during oxidation of phosphatidylcholine by peroxynitrite
Biochem Biophys Res Commun
Phospholipase action of platelet-activating factor acetylhydrolase, but not paraoxonase-1, on long fatty acyl chain phospholipid hydroperoxides
J Biol Chem
Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles
J Biol Chem
Paraoxonase-1 does not reduce or modify oxidation of phospholipids by peroxynitrite
Free Radic Biol Med
Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH
J Lipid Res
Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis
J Biol Chem
Paraoxonase 1 (PON1) deficiency in mice is associated with reduced expression of macrophage SR-BI and consequently the loss of HDL cytoprotection against apoptosis
Atherosclerosis
Paraoxonase 1 overexpression in mice and its effect on high-density lipoproteins
Biochem Biophys Res Commun
Comparative evaluation of the protective potentials of human paraoxonase 1 and 3 against CCl4-induced liver injury
Toxicol Lett
Paraoxonase 1 (PON1) attenuates macrophage oxidative status: studies in PON1 transfected cells and in PON1 transgenic mice
Atherosclerosis
Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: a possible role for lysophosphatidylcholine
Atherosclerosis
Effects of 5′ regulatory-region polymorphisms on paraoxonase-gene (PON1) expression
Am J Hum Genet
Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification
FEBS Lett
The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux
J Lipid Res
A polymorphism upstream from the human paraoxonase (PON1) gene and its association with PON1 expression
Atherosclerosis
High expressor paraoxonase PON1 gene promoter polymorphisms are associated with reduced risk of vascular disease in younger coronary patients
Atherosclerosis
Differential effects of smoking on myocardial infarction risk according to the Gln/Arg 192 variants of the human paraoxonase gene
Metabolism
Dietary modifications and gene polymorphisms alter serum paraoxonase activity in healthy women
J Nutr
Dietary determinants of serum paraoxonase activity in healthy humans
Atherosclerosis
Light, but not heavy alcohol drinking, stimulates paraoxonase by upregulating liver mRNA in rats and humans
Metabolism
Serum paraoxonase in alcohol abusers associated with alcoholic liver disease
Clin Chim Acta
The French paradox: possible involvement of ethanol in the protective effect against cardiovascular diseases
Nutrition
Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway
Atherosclerosis
Pomegranate juice polyphenols increase recombinant paraoxonase-1 binding to high-density lipoprotein: studies in vitro and in diabetic patients
Nutrition
C preserves the cardio-protective paraoxonase activity of high-density lipoprotein during oxidant stress
Arch Biochem Biophys
Retinoic acid reduces apoptosis and oxidative stress by preservation of SOD protein level
Free Radic Biol Med
Acai palm fruit (Euterpe oleracea Mart.) pulp improves survival of flies on a high fat diet
Exp Gerontol
The effect of micronised fenofibrate on paraoxonase activity in patients with coronary heart disease
Diabetes Metab
Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I
J Lipid Res
Structural and functional diversity of paraoxonases
Nat Med
Paraoxonase gene Gln192Arg (Q192R) polymorphism is associated with coronary artery spasm
Hum Genet
Association of paraoxonase 1 gene polymorphisms with risk of Parkinson's disease: a meta-analysis
J Hum Genet
Paraoxonase (PON)1 192R allele carriage is associated with reduced risk of inflammatory bowel disease
Dig Dis Sci
Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress
Arterioscler Thromb Vasc Biol
Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation
Circulation
The risk of coronary artery disease in population of Taiwan is associated with Cys-Ser 311 polymorphism of human paraoxonase (PON)-2 gene
Zhonghua Yi Xue Za Zhi (Taipei)
The paraoxonase-2-310 polymorphism is associated with the presence of microvascular complications in diabetes mellitus
J Intern Med
Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus
J Clin Endocrinol Metab
Cited by (223)
Do PON1–Q192R and PON1–L55M polymorphisms modify the effects of hypoxic training on paraoxonase and arylesterase activity?
2023, Journal of Sport and Health ScienceThe Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis
2024, International Journal of Molecular SciencesRole of paraoxonase 3 in regulating ENaC-mediated Na<sup>+</sup> transport in the distal nephron
2024, Journal of PhysiologyGenetics of Alzheimer’s Disease in the African American Population
2023, Journal of Clinical Medicine