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Current Opinion in Lipidology Aug 2020Studies have shown the three-member paraoxonase (PON) multigene family to be involved in the development of a large variety of diseases with an inflammatory component.... (Review)
Review
PURPOSE OF REVIEW
Studies have shown the three-member paraoxonase (PON) multigene family to be involved in the development of a large variety of diseases with an inflammatory component. Environmental factors such as lifestyle-related factors differ widely between populations and it is important to consider that their impacts may be exerted through the epigenetic mechanisms, which connect genes, the environment and disease development and are a potential therapeutic avenue.
RECENT FINDINGS
In the review period, very little was published on epigenetics of PON2 or PON3, mostly on their diagnostic value in cancer by measuring methylation levels of these genes. However, the picture is more promising with PON1. Here, several studies have linked the epigenetic regulation of PON1 to various metabolic processes and particularly to the development of several diseases, including stroke, heart disease, aortic valve stenosis and chronic obstructive pulmonary disease.
SUMMARY
Studies into the epigenetic regulation of the PON family are in their infancy. However, recent studies linking epigenetic regulation of PON1 to disease development will encourage further research and open up the possibility for new potential therapeutic interventions.
Topics: Animals; Aryldialkylphosphatase; Disease; Epigenesis, Genetic; Humans
PubMed: 32487820
DOI: 10.1097/MOL.0000000000000687 -
Current Pharmaceutical Design 2018Paraoxonase (PON) is a family of calcium-dependent hydrolases, which is related to many diseases. Elucidation of PON physiological roles, active center and all... (Review)
Review
BACKGROUND
Paraoxonase (PON) is a family of calcium-dependent hydrolases, which is related to many diseases. Elucidation of PON physiological roles, active center and all applications in medical fields are dependent on its substrates.
OBJECTIVE
The reports about PON substrates scattered in a long span of period are collected to afford clue for drug design, diagnosis of PON status and other academic purposes.
METHOD
PON substrates from 133 references are classified and compared. Structurally, PON substrates are generally classified as organic phosphorous esters, lactones and arylesters. Some phosphoramidates, organophosphorous obidoximes, aryl carboxylic acid amides and special fatty alcohol esters as PON substrates are also included.
RESULTS
The electron nature, steric hindrance and hydrophilicity of substrate substituents affecting the PON catalytic ability, binding ability and specificities are discussed. Drugs, prodrugs and naturally endogenous molecules in life processes activated or inactivate by PON are reviewed. Interestingly, some organophosphate and lactone substrates are preferably hydrolyzed by one of the PON1R192Q allozymes, and such a substrate is generally essential for differentiating the three PON1192R phenotypes by using a dual-substrate method. Intricately, some chiral substrates are hydrolyzed by PON stereoselectively.
CONCLUSION
As more substrates are synthesized and characterized, more facts about PON structure and catalytic properties (including PON active center and catalytic mechanism) will be revealed, and therefore the use of PON as a drug target or as an accurate disease marker will be achieved.
Topics: Animals; Aryldialkylphosphatase; Humans; Substrate Specificity
PubMed: 29237378
DOI: 10.2174/1381612824666171213102310 -
Seminars in Cancer Biology Jun 2019The paraoxonase (PON) gene family includes three proteins, PON1, PON2 and PON3. PON1 and PON3 are both associated with high-density lipoprotein (HDL) particles and exert... (Review)
Review
The paraoxonase (PON) gene family includes three proteins, PON1, PON2 and PON3. PON1 and PON3 are both associated with high-density lipoprotein (HDL) particles and exert anti-oxidant and anti-inflammatory properties. PON2 and PON3 are intracellular enzymes which modulate mitochondrial superoxide anion production and endoplasmic reticulum (ER) stress-induced apoptosis. The pleiotropic roles exerted by PONs have been mainly investigated in cardiovascular and neurodegenerative diseases. In recent years, overexpression of PON2 and PON3 has been observed in cancer cells and it has been proposed that both enzymes could be involved in tumor survival and stress resistance. Moreover, a lower activity of serum PON1 has been reported in cancer patients. This review summarizes literature data on the role of PONs in human cancers and their potential role as a target for antitumor drugs.
Topics: Animals; Apoptosis; Aryldialkylphosphatase; Biomarkers, Tumor; Diet; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Multigene Family; Neoplasms; Oxidative Stress; Risk Factors; Signal Transduction
PubMed: 29170064
DOI: 10.1016/j.semcancer.2017.11.013 -
Toxicology Jan 2019Organophosphates (OPs) are a class of chemicals commonly used in agriculture as pesticides, that can often lead to severe toxicity in humans. Paraoxonase-1 (PON1)... (Review)
Review
Organophosphates (OPs) are a class of chemicals commonly used in agriculture as pesticides, that can often lead to severe toxicity in humans. Paraoxonase-1 (PON1) belongs to a family of A-esterases and hydrolyses several OPs while also serving other biological roles. Two main genetic polymorphisms have been shown to affect enzymatic ability; an A > G transition in the 192nd position (192 Q/R, rs662), and an A > T at codon 55 (55 M/L, rs854560). In this review, we searched PubMed for relevant articles published from its inception till June 2018 and included publications from 1996 to 2018. We aimed to address the distribution of the polymorphisms in various populations, the way they affect enzymatic activity and the possible use of PON1 as a biomarker. The polymorphisms present great heterogeneity between populations, with the data being clearer over 192 Q/R, and this heterogeneity is related to the phylogenetic origins of each population. Concerning enzymatic activity, the different genotypes react better or worse to different OP substrates, with studies presenting a variety of findings. Detecting the "paraoxonase status" of an individual -referring to PON1 function- seems to be important in predicting OP toxicity, as studies have shown that some specific-genotype individuals present symptoms of toxicity in higher rates than others. We are strongly convinced that in order for the scientific community to reach a consensus over which polymorphisms confer susceptibility to toxicity and whether PON1 can eventually be used as a biomarker, more studies need to be carried out, since the data thus far does not seem to reach a universal conclusion.
Topics: Animals; Aryldialkylphosphatase; Gene Frequency; Humans; Organophosphates; Pesticides; Polymorphism, Genetic
PubMed: 30359673
DOI: 10.1016/j.tox.2018.10.012 -
Expert Opinion on Therapeutic Targets Jul 2013Paraoxonase-1 (PON1) is a Ca(2+) dependent, high-density lipoprotein-associated lactonase which is capable of retarding/inhibiting low-density lipoprotein (LDL)... (Review)
Review
INTRODUCTION
Paraoxonase-1 (PON1) is a Ca(2+) dependent, high-density lipoprotein-associated lactonase which is capable of retarding/inhibiting low-density lipoprotein (LDL) oxidation. LDL oxidation is believed to be central to the initiation and progression of atherosclerosis, therefore, PON1 is considered to be atheroprotective.
AREAS COVERED
Relevant literature on PON1 was identified in PubMed. Here, we discuss the background to research on PON1 in atherosclerosis, the evidence for and against PON1 being atheroprotective, potential mechanisms of this atheroprotection and current knowledge on human PON1 regulation.
EXPERT OPINION
Although current knowledge on PON1 indicates it to be atheroprotective, further clinical and basic studies are warranted to show that PON1 is causally linked to atherosclerosis, how it is atheroprotective and how it is regulated in vivo in humans.
Topics: Animals; Aryldialkylphosphatase; Atherosclerosis; Humans
PubMed: 23573876
DOI: 10.1517/14728222.2013.790367 -
Clinica Chimica Acta; International... Jan 2015Understanding the kinetics and function of paraoxonase 1 (PON1) is becoming an important issue in atherosclerosis. Low PON1 activity has been consistently linked with an... (Review)
Review
Understanding the kinetics and function of paraoxonase 1 (PON1) is becoming an important issue in atherosclerosis. Low PON1 activity has been consistently linked with an increased risk of major cardiovascular events in the setting of secondary prevention of coronary artery disease. Recent studies have shown that there is a specific interaction of myeloperoxidase (MPO)-apoAI-PON1 on HDL surface that seems to be germane to atherogenesis. MPO specifically inhibits PON1 and PON1 mitigates MPO effects. Surprisingly, very little is known about the routes by which PON1 gets integrated into HDL or its fate during HDL remodeling in the intravascular space. We have developed a method that assesses PON1 activity in the individual HDL subclasses with the aid of which we have shown that PON1 is present across the HDL particle range and preferentially in HDL3, confirming data from ultracentrifugation (UC) studies. Upon HDL maturation ex vivo PON1 is activated and it shows a flux to both smaller and larger HDL particles as well as to VLDL and sdLDL. At the same time apoE, AI and AII are shifted across particle sizes. PON1 activation and flux across HDL particles are blocked by CETP and LCAT inhibitors. In a group of particles with such a complex biology as HDL, knowledge of the interaction between apo-lipoproteins, lipids and enzymes is key for an increased understanding of the yet multiple unknown features of its function. Solving the HDL paradox will necessitate the development of techniques to explore HDL function that are practical and well adapted to clinical studies and eventually become useful in patient monitoring. The confluence of proteomic, functional studies, HDL subclasses, PON1 assays and zymogram will yield data to draw a more elaborate and comprehensive picture of the function of HDL. It must be noted that all these studies are static and conducted in the fasting state. The crucial phase will be achieved when human kinetic studies (both in the fasting and post-prandial states) on HDL-PON1, apoA-I and lipid fate in the circulation are carried out.
Topics: Animals; Aryldialkylphosphatase; Humans; Lipoproteins, HDL
PubMed: 25261854
DOI: 10.1016/j.cca.2014.09.016 -
American Journal of Cardiovascular... 2010
Topics: Aryldialkylphosphatase; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Trimetazidine; Vasodilator Agents
PubMed: 20928960
DOI: 10.2165/11539490-000000000-00000 -
Nutrients Jul 2022Paraoxonase 1 (PON1) is an antioxidant enzyme attached to HDL with an anti-atherogenic potential. It protects LDL and HDL from lipid peroxidation. The enzyme is... (Review)
Review
Paraoxonase 1 (PON1) is an antioxidant enzyme attached to HDL with an anti-atherogenic potential. It protects LDL and HDL from lipid peroxidation. The enzyme is sensitive to various modulating factors, such as genetic polymorphisms as well as pharmacological, dietary (including carotenoids), and lifestyle interventions. Carotenoids are nutritional pigments with antioxidant activity. The aim of this review was to gather evidence on their effect on the modulation of PON1 activity and gene expression. Carotenoids administered as naturally occurring nutritional mixtures may present a synergistic beneficial effect on PON1 status. The effect of carotenoids on the enzyme depends on age, ethnicity, gender, diet, and PON1 genetic variation. Carotenoids, especially astaxanthin, β-carotene, and lycopene, increase PON1 activity. This effect may be explained by their ability to quench singlet oxygen and scavenge free radicals. β-carotene and lycopene were additionally shown to upregulate PON1 gene expression. The putative mechanisms of such regulation involve PON1 CpG-rich region methylation, Ca(2+)/calmodulin-dependent kinase II (CaMKKII) pathway induction, and upregulation via steroid regulatory element-binding protein-2 (SREBP-2). More detailed and extensive research on the mechanisms of PON1 modulation by carotenoids may lead to the development of new targeted therapies for cardiovascular diseases.
Topics: Antioxidants; Aryldialkylphosphatase; Carotenoids; Gene Expression; Lycopene; beta Carotene
PubMed: 35889799
DOI: 10.3390/nu14142842 -
Frontiers in Bioscience (Landmark... Jan 2021Some organophosphorus compounds (OPs), which are used in the manufacturing of insecticides and nerve agents, are racemic mixtures with at least one chiral center with a... (Review)
Review
Some organophosphorus compounds (OPs), which are used in the manufacturing of insecticides and nerve agents, are racemic mixtures with at least one chiral center with a phosphorus atom. Acute exposure of humans to these mixtures induces the covalent modification of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) and causes a cholinergic syndrome or organophosphate-induced delayed polyneuropathy syndrome (OPIDP). These irreversible neurological effects are due to the stereoselective interaction of the racemic OPs with these B-esterases (AChE and NTE) and such interactions have been studied in vivo, ex vivo and in vitro, using stereoselective hydrolysis by A-esterases or phosphotriesterases (PTEs) and the PTE from Pseudomonas diminuta, and paraoxonase-1 (PON1) from mammalian serum. PON1 has a limited hydrolytic potential of the racemic OPs, while the bacterial PTE exhibits a significant catalytic activity on the less toxic isomers P(+) of the nerve agents. Avian serum albumin also shows a hydrolyzing capacity of chiral OPs with oxo and thio forms. There are ongoing environmental and bioremediation efforts to design and produce recombinants as bio-scavengers of OPs.
Topics: Animals; Aryldialkylphosphatase; Catalysis; Hydrolysis; Mammals; Organophosphorus Compounds; Phosphoric Triester Hydrolases; Stereoisomerism
PubMed: 33049692
DOI: 10.2741/4916 -
Journal of Biosciences 2021Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also... (Review)
Review
Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also demonstrated the significance of PON2 in the manifestation of cardiovascular and several other diseases, and hence, it is considered an important biomarker. Recent findings of its expression in brain tissue suggest its potential protective effect on oxidative stress and neuroinflammation. Polymorphisms of PON2 in humans are a risk factor in many pathological conditions, suggesting a possible mechanism of its anti-oxidative property probably through lactonase activity. However, exogenous factors may also modulate the expression and activity of PON2. Hence, this review aims to report the mechanism by which PON2 expression is regulated and its role in oxidative stress disorders such as neurodegeneration and tumor formation. The role of PON2 owing to its lactonase activity in bacterial infectious diseases and association of PON2 polymorphism with pathological conditions are also highlighted.
Topics: Aryldialkylphosphatase; Brain; Humans; Neoplasms; Oxidative Stress; Polymorphism, Genetic
PubMed: 34987135
DOI: No ID Found