PON1: Increase Longevity And Detox Pesticides with 99+ Ways To Increase Paraoxonase 1

Paraoxonase 1: I've Got 99 Problems But Paraoxon Ain't 1

 
olive oil pon1
 

Paraoxonase 1 (PON1) is an enzyme that plays a role in most diseases.

In this post, we will discuss how you can use PON1 to improve overall health, longevity, and detox mechanisms.  

Contents:

  1. Basics Of Paroxonases
  2. Benefits Of PON1
  3. How To Increase PON1
  4. What Decreases PON1?
  5. PON1 Activity And Acetylcholine Hypersensitivity
  6. Mechanism Of Action
  7. Genetics
  8. More Research

Basics Of Paroxonases

Paraoxonase/arylesterase 1 (PON1) also known as A esterase (homocysteine thiolactonase) or (aryldialkylphosphatase 1) is an enzyme that works on Paraoxonase (PON), Arylesterase (ARE), and diazoxonase. R

There are 3 PON enzymes and PONs have many very important functions in the body as they: R

  1. Inactivate pro-oxidant and pro-inflammatory mediators
  2. Metabolize of certain drugs and xenobiotics
  3. Regulate of cells growth

PON1 is found outside cells and in HDL (more below), while PON2 and PON3 have activities inside the cell, mitochondria, and endoplasmic reticulum. R R

Simply put, PON1 is this enzyme that wraps itself around the outside of cells and acts as an antioxidant meaning it protects the cells from getting damaged.

Having more PON1 has shown to be beneficial in most diseases.

Benefits Of PON1

1. Fights Vascular Disease

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5195879/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5195879/

 

Having low PON1 levels and a genetic predisposition in PON1 can increase the risk for heart disease. R

For example, low PON1 paraoxonase and arylesterase activities are both associated with increased major adverse cardiovascular events risk. R

This is because PON1 acts as an antioxidant that can help prevent vascular disease. R

For example, higher PON1 activity can protect against Coronary Artery Disease (CAD). R

Also, higher PON1 may reduce the risk of heart attack and prevent systemic vasculitis. R R

Higher blood High-Density Lipoprotein (HDL) levels and lower Low-Density Lipoprotein (LDL) levels are inversely correlated with atherosclerosis. R

PON1 is the reason why HDL is protective, as PON1 protects HDL and LDL from being oxidized (PON1 makes them more resistant to oxidation). R R R

PON1 may also protect the vascular system by reducing high Homocysteine (Hcy) levels.  R

It has been shown that PON1 may also protect against low Apolipoprotein E (ApoE) levels, such as those with ApoE4 polymorphisms. R R

Loss PON1 activity may also blunt the production of Nitric Oxide (NO) in the vascular system. 

Technical of PON1 activities: R

  • Prevention of LDL and cell membrane oxidation
  • Prevention of LDL Glycation
  • Prevention of diabetes development
  • Reduction of macrophage oxidative stress
  • Promotion of macrophage RCT
  • Normalisation of endothelial function
  • Metabolism of homocysteine thiolactones
  • Prevention of LCAT oxidative inactivation
  • Disposal of toxic apoptosis products
  • Prevention of apoptosis
  • Reduction of monocyte macrophage inflammatory response

2. Prevents Oxidative Stress And Inflammatory Responses

As mentioned above, PON1 has antioxidant properties.

It battles inflammatory stress as inflammation can negatively affect (inactivate) PON1 activity. R R R

Technical: R

  • In the immune system, adding unesterified cholesterol to human monocyte/macrophages causes release of highly Procoagulent Microvesicles (UCMV) causing cell death.
  • MVs contain damage-associated molecular patterns (DAMPs) which are endogenous danger signals which stimulate an immune response.
  • UCMVs induce mitochondrial production of superoxide and peroxides and contain malondialdehyde-like peroxidised epitopes.
  • he incubation of UCMVs with HDL or purified PON1 detoxifies the malondialdehyde DAMPs and prevents the immune response.
  • This is a potentially novel atheroprotective role of PON1 but also has wider implications of PON1 as a non-inflammatory remover of apoptosis induced cellular debris

3. Supports Detox Mechanisms

 
"Upon entering the human body, the parent OP organophosphorothioates are either detoxified by specific cytochrome P450s (and eliminated in the urine) or are converted to their highly toxic oxon forms. The highly toxic oxons interact with serine active-site enzymes (e.g. AChE and BChE) creating a covalent bond with their active site serine that ages to an irreversible inhibitor of the enzyme. The adducted protein is stable and will remain in circulation until degradation, which depends on the protein’s half-life in circulation (11 days for plasma BChE and 33 days for red blood cell AChE). The oxons can also undergo spontaneous or enzymatic (i.e. PON1) hydrolysis resulting in the formation of DAP metabolites and an OP-specific leaving group. These metabolites do not show inhibitory properties and are eliminated in the urine." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916371/

"Upon entering the human body, the parent OP organophosphorothioates are either detoxified by specific cytochrome P450s (and eliminated in the urine) or are converted to their highly toxic oxon forms. The highly toxic oxons interact with serine active-site enzymes (e.g. AChE and BChE) creating a covalent bond with their active site serine that ages to an irreversible inhibitor of the enzyme. The adducted protein is stable and will remain in circulation until degradation, which depends on the protein’s half-life in circulation (11 days for plasma BChE and 33 days for red blood cell AChE). The oxons can also undergo spontaneous or enzymatic (i.e. PON1) hydrolysis resulting in the formation of DAP metabolites and an OP-specific leaving group. These metabolites do not show inhibitory properties and are eliminated in the urine." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916371/

 

PON1 helps detox:

  • Cigarette smoke R
  • Heavy metals (see more below)
  • Homocysteine Thiolactone R
  • Lactones -  found in funguses, ascorbic acid, kavain, nepetalactone, gluconolactone, hormones (spironolactone, mevalonolactone), enzymes (lactonase), neurotransmitters (butyrolactone, avermectins), antibiotics (macrolides like erythromycin; amphotericin B), anticancer drugs (vernolepin, epothilones), phytoestrogens (resorcylic acid lactones, cardiac glycosides) R
  • Organophosphates (pesticides, insecticides, and nerve agents, such as paraoxon, chlorpyrifos, oxon, parathion, diazoxon, sarin, VX, soman, Phenyl acetate, 4- nitrophenyl acetate, 5-thiobutil butyrolactone (TBBL), Dihydrocoumarin) R R R R
    • Recombinant PON1 has shown to directly protect the mice against these lethal exposures of OP.
  • Oxidized LDL R

The way POTS  detoxes OP's is by increasing its ability to be more water soluble. R

Low PON1 has also been associated with "dippers flu" (which is dipping sheep in pesticides/fungicides) which causes chronic central and peripheral nervous system abnormalities. R R 

4. Linked To Chemical Sensitivities

Multiple Chemical Sensitivity (MCS) has been associated with mutations in PON1. R R

Although it is important to note that the evidence is weak and other studies have shown PON1 not to be a strong factor in MCS. R R

5. Protects Development And Plays A Role In Autism

During development, PON1 activity is very low and progressively increases until reaching adult levels at 6 to 15 months of age. R

This means children are more sensitive to OP toxicity at birth. R

For example, early exposure to pesticides can increase the chance of heart disease. R

Decreased PON1 activity has been linked to childhood obesity (with alterations in leptin, adiponectin, and resistin levels) and metabolic syndrome. R R

Children that are exposed to organophosphates (with lower PON1 levels) may have lower IQ levels. R R R

OPs on neurodevelopment may lead to (transgenerational) permanent cognitive problems and developement of neurodegenerative diseases. R

For example, children with autism have shown to have lower PON1 levels. R

6. Improves Diabetes And Metabolic Syndrome

PON1 may help with Type 1 and Type 2 Diabetes (T1D and T2D, respectively). R

Expression of human PON1 can prevent diabetes development in mice through its antioxidant properties and the stimulation of beta-cell insulin release. R R

Mutations in PON1 have been associated with insulin resistance, diabetic neuropathy and diabetic retinopathy. R R

3 months of Ginger supplementation was able to improve T2D markers (glucose, insulin, HbA1c, hsCRP, MDA and PON1). R

7. Plays A Role In Polycystic Ovary Syndrome

Mutations in PON1 are common in patients with Polycystic Ovary Syndrome (PCOS). R

For example,  lower levels of PON1 have been seen in untreated patients with PCOS. R R

Treatment with Metformin was able to restore PON1 levels. R

8. Plays A Role In Menopause And Osteoporosis

Lower PON1 levels may contribute to the development of Postmenopausal Osteoporosis and Cardiovascular Disease (PMOP). R

This may be because Estrogens can also regulate homocysteine and PON1 levels. R

9. May Help Prevent Alzheimer’s Disease And Dementia

Mutations in PON1 have been significantly associated with Alzheimer's Disease (AD). R

For example, in a study with 100 healthy individuals and 50 patients, controls and patients had statistically significant polymorphisms in rs705379R

Response to nutrients that increase PON1 may be lower in those that are ApoE4, compared to ApoE3. R

Lower levels of PON1 have also been associated in those with Vascular Dementia (VD). R R

In dementia, insulin resistance (high HOMA IR index) has been seen and PON1 can enhance insulin production and release. R

10. Could Protect Against Parkinson's Disease 

The metabolism of environmental neurotoxins and may be responsible for neurodegeneration as seen in Parkinson's Disease (PD). R

Mutations in the PON1 gene may increase the risk of developing early-onset PD by 5.15x. R

Mutations in PON1 can also increase susceptibility of developing environmentally induced-PD after OP exposure. R R

11. Plays A Role In Mood, Depression And Anxiety

 
depression pon1
 

Mutations in PON1 may contribute to Bipolar I Disorder. R

For example, lowered PON1 activity has also been significantly associate with bipolar disorder and depression in women (possibly by higher bacterial infections, higher homocysteine levels, and increased neurotoxicity). R R

PON1 activity may also contribute to toxin-induced depression. R

For example, mutations in PON1 may make women more susceptible to depression after exposure to toxins. R

Also, low PON1 levels may contribute to anxietyR R

For example, those with General Anxiety Disorder (GAD) had higher levels of serum levels of Lipid Hydroperoxide (LOOH), but lower levels of PON1. R

12. May Help Renal Failure And Glomerulonephritis

For example, chronic renal failure patients on dialysis show lower levels of PON1 activity. R

Zinc and Vitamin C supplementation may help reduce oxidation in those with kidney problems and low loves of PON1. R R

13. May Be A Biomarker For Liver Impairment

As PON1 is manufactured and regulated by the liver, decreased activity of PON1 can cause problems with proper liver function. R R

For example, during inflammation, decreased PON1 expression in the liver has been linked to reduced antioxidant levels and diseases such as Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). R

14. Plays A Role In Rheumatoid Arthritis 

Mutations in PON1 have been implicated with increased risk of Rheumatoid Arthritis (RA). R R

Low levels on PON1 may be reversed in RA by supplementing Soy Protein or Isoflavones. R 

Also in a double-blind study in women with RA, Fish Oil was able to improve PON1 levels. R

In a pilot study, Pomegranate Extract supplementation was able to improve PON1 levels and RA symptoms. R

15. May Protect Against The Standard American Diet

Higher PON1 levels may protect against a Standard American Diet (SAD = high sugar + high fat diet). R

For example, by increasing PON1, supplementation of Cornelian Cherry had a neuroprotective and antioxidative effect on animal models eating a diet high in fat and sugar. R

Selenium supplementation may also help with reduced PON1 levels from a high fat diet. R

High PON1 levels may also protect against a diet high in cholesterol. R

16. Prevents Metal Toxicities

In animal studies and cell cultures, there is evidence that all metals reduce PON1 activity - Cadmium, Mercury, iron, zinc, lead, aluminum, cerium, samarium, Gadolinium, lanthanum, yttrium, manganese, Copper, cobalt, silver, and Arsenic. R

A few caveats: R

  • Selenium can (mostly) counteract Mercury's effects on PON1
  • A diet high in Iron may also lower PON1
  • In iron-deficient anemia (as said above or discussed more below), iron supplementation helps improve PON1 activity
  • In human studies, Copper and Zinc seem to have very little decrease on PON1

The good news is that PON1 may help protect against oxidative stress from heavy metal toxicity. R

For example, Onion Extract supplementation was able to increase PON1's antioxidant resistance against Mercury-induced oxidative stress. R 

In another study, dietary supplementation with Selenium and Vitamin E was able to partially improve against Mercury's reduction ofPON1 activity. R

17. Plays A Role In Anemia

PON1 levels have shown to be lower multiple anemias. R R

Iron supplementation has shown to improve PON1 levels in anemia. R

18. Prevents Stroke 

PON1 may be a potential clinically useful biomarker for Ischemic Stroke (IS) diagnosis. R R R R

Increasing PON1 may be beneficial for stroke. R

For example, use of the supplement ALAnerv (two pills/day for two weeks) resulted in a significant increase in PON activity in post-acute stroke patients. R

19. Protects The Thyroid

PON1 levels may contribute to hypothyroidism as serum PON1 activity has shown to be decreased in thyroid dysfunction. R

For example, organophosphates can disrupt thyroid function (e.g. ↑ TSH,  ↓T4, ↓TT3 levels) by reducing PON1 activity. R

20. May Improve Tolerance To Hypoxia

PON1 may may improve tolerance to hypoxiaR

For example, consistent higher expression levels of PON1 have shown to be an effective biomarker for altitude adaptation. R

21. Destroys Biofilms, Infections, And Plays A Role In Sepsis

 
PON1 infection biofilm
 

PON1 has Biofilm-Inhibiting properties against Pseudomonas aeruginosa (PON1 inhibits quorum sensing). R

Loss of PON1 may increase the risk of infection, as it can allow for Bacterial Quorum Sensing. R

Infection with Visceral Leishmaniasis (VL) can also reduce PON1 activity. R

Low PON1 activity is associated with higher death rates in surgical patients with sepsis. R

22. Plays A Role In Cancer

PON1  is beneficial in inhibiting some cancers, but in others, it may promote the growth of other cancers (metastasis). R R

PON1 expression may play a role in these cancers:

  • Brain R
  • Breast R 
  • Colorectal R
  • Esophagus R R R
  • Liver R
  • Lung R R
  • Ovarian R
  • Pancreatic R
  • Prostate R

23. May Reduce Psoriasis

Mutations in PON1 can significantly predispose to the development of Psoriasis. R R

It has been reported that patients with psoriasis may have lower PON1 level and thus lower antioxidant activity (such as SOD and CAT). R

Treatment with etanercept was able to restore PON1 levels and reduce psoriasis symptoms. R

24. Associated With Longevity 

Higher levels of PON1 have been associated with longevity. R

This may be attributed to PON1's ability to act as an antioxidant. R

For example, A allele carriers of the SNP rs854560 have a higher chance of becoming centenarians vs G allele carriers. R

Although some analysis have found no association with PON1 mutations and longevity, it has been noted that PON1 activity on longevity may be dependent on population and environment. R

Elimination of PON1 can make cells senescent. R

25. Implicated In Systemic Lupus Erythematosus

Mutations in PON1 have been implicated with increased risk of Systemic Lupus Erythematosus (SLE). R

26. Plays A Role In Amyotrophic Lateral Sclerosis (ALS)

Mutations in PON1 activity have been implicated in Amyotrophic Lateral Sclerosis (ALS). R

Reductions in PON1 organophosphate detoxification (reduction) is associated with ALS. R

27. Ameliorates Asthma

PON1 activity has been shown to be significantly lower in asthmatic patients. R

Increasing PON1 expression in asthmatic patients may be beneficial to reduce inflammation. R

For example, in asthmatic animal models overexpressing PON1, there was decreased inflammatory cytokines, IgE, IgG1, MDA activity, but increased IgG2a, IFN-γ, glutathione (GSH). R

28. Plays A Role In Chronic Pancreatitis

Lower PON1 levels have been seen in animal studies with acute pancreatitis. R

This (lower PON1 levels) has shown to be accurate as well in patients with Chronic Pancreatitis. R

29. Combats Crohn’s Disease And Irritable Bowel Disease

PON1 is reduced in patients with Irritable Bowel Disease (IBD) and can indicate disease activity, inflammation severity, and anemia. R

Mutations in PON1 have shown predispose Ashkenazi Jewish population to Crohn’s Disease (CD) and Ulcerative Colitis (UC). R

PON1 may be a key factor involved in intestinal mucosal and peripheral defense against oxidative stress in CD. R

30. Plays A Role In Sarcoidosis

In multiple studies, decreased levels of PON1 have been seen in patients with sarcoidosis. R R

This is probably due to increased oxidative stress. R

31. May Rectify Erectile Dysfunction

 
pon1 male sexual erectile dysfunction
 

Increasing PON1 may be beneficial for male sexual health. R

For example, compared to healthy men, patients with Erectile Dysfunction (ED) have significantly lower levels of PON1 activity. R

32. Plays A Role In Multiple Myeloma

Significantly lower levels of PON1 and been seen in multiple myeloma patients in comparison to healthy subjects. R R

This may lead to increased oxidative stress and lipid peroxidation in multiple myeloma. R

33. Protects The Eyes

PON1 expression and plasma is normally higher in the eyes. R

In those with cataracts, low PON1 expression has been seen. R

Mutations in PON1 have been implicated with Age-related Macular Degeneration (AMD). R

34. May Help Ankylosing Spondylitis 

PON1 levels have been shown to be significantly reduced in patients with ankylosing spondylitis. R

35. May Play A Role In HIV

Lower PON1 levels in HIV patients may increase the risk of atherosclerosis during use of protease inhibitors (PIs). R

Lower PON1 activity in HIV patients may also be a marker for the metabolic syndrome. R

How To Increase PON1

 
 

Top 5 Ways To Increase PON1:

  1. Chokeberries
  2. Genistein
  3. Mediterranean Diet (high in Olive Oil)
  4. Pomegranate
  5. Vitamin E

Lifestyle/Diet:

Supplements:

Probiotics/Prebiotics/Symbiotics:

Hormones

  • Erythropoietin beta - ↑ ~23% in predialysis patients with chronic renal disease and anemia R
  • Hormone Replacement Therapy (Estrogen and methoxyprogesterone acetate) - ↑10% in diabetic post-menopausal women R

Drugs:

  • Aspirin - ↑ 13% in low doses R R R
  • Carvedilol R
  • Ciprofibrate R 
  • Cyclophosphamide R
  • Dexamethasone R
  • D-4F R
  • Eplerenone - ↑ 60% R
  • Etanercept R
  • Ezetimibe R
  • Fenofibrate - ↑ 70% R
  • Gemfibrozil -  ↑ 18–59% R
  • Glibenclamide - only in diabetics, decreased/no change to control PON1 R
  • Gliclazide R
  • Glimepiride - only in diabetics, decreased/no change to control PON1 R
  • Metformin R
  • Probucol - ↑ 50% R
  • Rosiglitazone - ↑ 9–13% H, 21-67% A R R R
  • Some Statins (e.g. simvastatin, pitavastatin, or atorvastatin and its metabolites - p-hydroxy and o-hydroxy) - ↑5–23% R R

Pathways:

  • ApoA1 R
  • ApoE - ↑ 40-96% R
  • IL-6 R
  • LXR R
  • NF-kB inhibition R
  • PKA R
  • PPAR-delta R
  • PPAR-gamma R
  • Sp1 R
  • SREBP-2 R
  • uPA inhibition R

Other:

  • Graptopetalum paraguayense R
  • Ovarian Stimulation R

What Decreases PON1?

The response of PON1 activity to dietary supplements is modified by APOE gene polymorphisms for Quercetin, Vitamin E, and betaine- and methionine-restricted diets R R R

What Else Reduces PON1 Expression:

  1. Bile R
  2. Certain Antibiotics (e.g ampicillin, ciprofloxacin and clindamycin, but not rifamycin) R
  3. Cholesterol - affects males more than females R R R
  4. Cholinergic Muscarinic Antagonist (e.g. atropine) R
  5. Copper Deficiency R
  6. Diet with High Carbohydrates + High Fats - fasting may help reverse this reduction R
  7. Endotoxemia/Lipopolysaccharides R
  8. Fluvastatin R
  9. FXR R
  10. Gabapentin R
  11. Ginseng R
  12. Heavy Drinking - ↓ 53-72%R R
  13. Heavy Metals (e.g. MercuryR
  14. High Fat Diet R
  15. High Suchegar Diet R
  16. Hydrogenated Oils (e.g. canola, palm) R
  17. Inflammation (e.g. TNFα, IL-1β, IL-6) and Oxidative Stress R R R
  18. Iron Deficiency Anemia R
  19. Leptin R
  20. Menopause R
  21. Nandrolone Decanoate R
  22. Olanzapine R
  23. Omega 6's R
  24. Oral Contraceptives (e.g. desogestrel or levonorgestrel in combination with ethinyl estradiol) - decreases liver PON1, but increases serum PON1 R
  25. Organophosphates (pesticides, insectisides, etc) R
  26. PKC R
  27. Sleep Apnea R
  28. Smoking (incl. nicotine) R R

PON1 Activity And Acetylcholine Hypersensitivity

I've noticed the more I've been exposed to toxins and messed up my detox mechanisms, I have become more sensitive to the downsides of high Acetylcholine (ACh) levels.  

This sensitivity to ACh may be from a buildup of Organophosphates (OPs) and Heavy Metals (among other things), which are two very potent Acetylcholinesterase Inhibitors (AChEI's). R R R R

For example, OPs can cause different health problems due to the inhibition of acetylcholinesterase at nerve endings, which leads to the accumulation of ACh neurotransmitter and consequently over-stimulation of Muscarinic and Nicotinic receptors. R R

Rats injected with purified PON1 from rabbit serum were more resistant to acute cholinergic activity than the control rats. R

Dysregulation of choline has be seen in those PON1 mutations and low Butyrylcholinesterase (BuChE) activity. R R

Also those with lower PON1 levels and higher ACh levels more commonly exhibit anxiety. R

I used to be so sensitive I could not eat any foods with choline (e.g. blueberries, eggs, etc - see ACh post for more). 

I have noticed that increasing PON1 has contributed to reducing my ACh hypersensitivity.

Another post will be written about all the mechanisms I believe behind ACh hypersensitivity, as PON1 is just part of the puzzle. 

Mechanism Of Action

 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503369/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503369/

 

Simple:

  • Increases CATR
  • Increases GLUT4 R
  • Increases GSH-Px R
  • Increases SIRT1 R
  • Increases SOD R
  • Reduces CCL2 R
  • Reduces Hcy R
  • Reduces IRS-1 R
  • Reduces MCP-1 R
  • Reduces ox-LDL R

Advanced:

  • PON1 contains three cysteines (Cys42, Cys284, and Cys353) of whom two (Cys42 and Cys353) generate a disulfide bond...the replacement of either Cys42 or Cys353 by alanine leads to loss of the catalytic activity and substantial reduction of enzyme secretion...change of Cys284 to alanine or serine results in reduction but remaining a residual paraoxonase and arylesterase activities. R
  • In PON1, there are two Ca2+-binding sites, one of which has a high affinity and is needed for enzyme stabilization while another is necessary for hydrolytic activity...removal of Ca2+ leads to irreversible loss of the enzymatic activity and destabilization. R
  • PON1 is a glycoprotein, with Asn253 and Asn324 as predicted glycosylation sites. R
  • PON1 (dependent on Ca2+) is synthesized in the liver and secreted into the serum as an HDL-associated protein (PON1 protein binding to HDL through the A1 and J apoproteins making the enzyme became more stable). R
  • HDL isolated from healthy individuals increases NO bioavailability (improving endothelial function) via interaction with the SR-B1 receptor when incubated with cultured endothelial cells. R
  • PON1 could initially bind to small-diameter HDL particles (HDL3) that are converted to larger HDL2...this increase in particle size is a consequence of the metabolism of HDL that leads to an enrichment of cholesterol in the lipid core. R
  • The mechanism by which PON1 retards LDL oxidation is unproven but appears to involve the hydrolysis of the truncated oxidized fatty acids from phospholipid, cholesterylester and triglyceride hydroperoxides resulting in the production of lysophospholipids, cholesterol, diglyceride and oxidized fatty acids. R
  • It is also found in the kidneys, chondrocytes, enterocytes, eye lens and retinal layers, skin epidermis, stomach, tongue and trachea. R
  • PON1 is involved in the detoxification of homocysteine (Hcy)-thiolactone, a reactive metabolite that, through a process of N-homocysteinylation, affects the structure and function of proteins and lipoproteins including HDL. R
  • Some possible mechanisms of polyphenols on PON1:
    • Upon ligand binding, AhR translocates to the nucleus and forms a heterodimer with the ARNT...the AhR/ARNT heterodimer binds to xenobiotic responsive elements (XREs) within the PON1 promoter (_126 and _106 region) and induces an upregulation. R
    • PON1 translocation through SREBP-2 from the endoplasmic reticulum to the nucleus, where interacts with sterol responsive elements-like sequence on the PON1 promoter. R
    • MAPKs regulate PON1 activity...polyphenols may stimulate PON1 transcription through the activation of JNK or acting as a scavenger by inhibiting ROS production and oxidation. R
  • PON1 can decrease oxidative stress in serum lipoproteins, macrophages, and atherosclerotic lesions. R R
  • PON1 can make lactones more water soluble (e.g. the antibacterial prodrug prulifloxacin), endogenous compounds (e.g. lactone metabolites of arachidonic acid, or homocysteine thiolactone), and N-acyl-homoserine lactones, which are quorum sensing signals of pathogenic bacteria. R R
  • PON1 hydrolyzes the metabolites, not the parent compounds of insecticides. R
  • Histidine residues (His115, His134, His155, His243) and Trp281 are involved in the esterase enzymatic activity of PON1. R

Genetics

ApoE

Response to nutrients that increase PON1 may be lower in those that are ApoE4, compared to ApoE3. R R

See ApoE post.

PON1

rs662 (I'm CC)  

  • C Alleles
    • C allele - highest PON1 activity R
    • CC alleles + ACE DD - 337% higher risk of CAD compared to the population without this polymorphic association...the association between AA + ACE GG was linked to an even higher risk R
    • C allele - Leptin may mediate fat accumulation during childhood related to prenatal pesticide exposure in children. R 
    • CC alleles - higher PON1 activity and increased TSH activity when exposed to organophosphates in Mexican population R
    • CC alleles - AA homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD R
    • CC alleles - associated increased longevity in Bama Zhuang population R
    • C alleles -  may benefit to a greater extent from intake of vegetables and thus be more effectively protected from ischemic stroke R
    • C allele - greater risk of myocardial infarction (MI) under the age of 45  R
    • CC  alleles - homozygotes associated with increased risk for stroke, followed by G/A heterozygotes, the GG R
    • Each A allele - increased associated with depression after toxin exposure; per‐allele odds ratio 1.22 (95% confidence interval: 1.05 to 1.41) R
    • CC alleles - hydrolyse paraoxon more rapidly, but hydrolysed diazoxon more slowly than GG R
    • CC and GA alleles - significant association between bipolar I disorder R
    • CC alleles have higher association with Asthma R
    • CC alleles - associated with an increased risk of AEG with Chinese smokers vs CC alleles R
    • C allele - increased anxiety R
    • C allele - increased risk of Alzheimer's R
  • T Alleles
    • TT alleles -  lowest PON1 activity, followed by AG carriers and the AA carriers R
    • TT alleles - higher risk (2.318x for GG or 1.485x for G) of ankylosing spondylitis R
    • Each T allele - was associated with 28% higher risk of total Ischemic Stroke (p = 0.008) and 32% higher risk of large artery atherosclerosis subtype (LAA) (p = 0.01) independent of vegetable consumption R
    • T allele - those treated with statins exhibited improvement in glucose metabolism, especially in insulin secretion, suggesting the importance of genotyping PON1 Q192R to identify those who could benefit from statin therapy R 
    • T allele - increased risk of Rheumatoid Arthritis when having a mutation in BuChE R
    • T allele - carbohydrate rich diet reduces LDL levels vs saturated fat-enrichedand monounsaturated fat-enriched diets R
    • TT alleles - hydrolyse diazoxon faster than AA alleles R
    • TT and TC alleles - associated with male infertility R
    • T allele - higher rate of IBD in Ashkenazi patients R
    • TT alleles - associated with an significantly decreased risk of Esophagogastric junction adenocarcinoma (AEG) with Chinese smokers vs CC alleles R

rs854560

  • A Alleles
    • A allele - highest PON1 activity R
    • A allele - significantly increased (p  0.012) centenarians in comparison to that found in young people R
    • A  allele (GA or AA individuals) - significantly increased association of becoming centenarians vs those with Q allele R
    • AA alleles - higher association with CAD in North Indian populations R R
    • AA alleles exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk R
    • A allele + ApoE ε4 act synergistically to increase the risk of SLE by 1.47 times (p = 0.038) R
    • A allele - higher risk for psoriasis and high levels of MDA, APOB and LP(a), a high APOB/APOA1 ratio and low ARE activity R
    • AA and TA alleles - significant association between bipolar I disorder R
  • T Alleles
    • TT alleles - ~2x higher risk of CAD vs AA alleles R
    • TT alleles - Cigarette smokers with TT had an increased risk of CAD than did smokers with the A allele (AA + AT) and nonsmokers with the TT genotype R
    • TT alleles - higher association with CAD in Brazilian Caucasian and North Indian populations R R
    • T allele - higher PON1 activity after consumption of juices R
    • TT alleles - associated more severe insulin resistance vs A allele, because they were more overweight and had the highest levels of triglycerides and blood pressure and the lowest values of plasma high-density lipoprotein cholesterol R
    • T allele - higher rate of IBD in Ashkenazi patients R
  • Unknown allele - Significant interaction with population density for marker rs854560 in ALS R

rs705379 (I have a deletion) - is the strongest known predictor of PON1 gene expression and protein levels R

  • G Alleles
    • G allele - PON1 (arylesterase) is upregulated R
    • Each G allele - increases (2.53 mm Hg) Mean Arterial Blood Pressure at a younger age (<50 y/o), no effect on over 50 y/o R
  • A Alleles
    • AA allele - PON1 (arylesterase) is less R
    • AA children had lower IQ when exposed to organophosphates R
    • A allele - more common in Alzheimer’s disease R

rs72552787 (I'm TT)

rs61736513

rs1000364356 

rs987539

  • C > T - associated with susceptibility to sporadic ALS R
  • Association with lupus R

rs2074351

  • Associated with susceptibility to sporadic ALS R

rs7085381

  • A Allele
    • A allele - higher risk of macular degeneration (increase in luciferase activity of approximately twofold) R

rs2057681

  • Associated with significant increase in paraoxonase activity, but also associated with significant decrease in arylesterase activity R

rs3735590

  • T Allele
    • TT alleles - has higher PON1 expression R
    • TT or CT genotypes had a significant lower risk of ischaemic stroke and thinner carotid artery IMT than subjects with the CC R
  • C Allele
    • CC alleles - has lower PON1 expression R

rs4242382 (I'm GG)

  • A Allele
    • AA alleles - increased risk for prostate cancer with exposed to organophosphates R
    • AA alleles - increased risk for prostate cancer (3.15x) R

rs854555 (I'm AA)

  • A Allele
    • A allele + A rs662 - significantly correlated to the increased susceptibility to osteonecrosis of femoral head R

rs854571 (I'm CT)

  • T Allele
    • T allele - preventative factor for stroke R
    • T allele - lower PON1 expression R
    • T allele - more common in Parkinson's Disease R

rs854572

  • C Allele
    • C allele - may be a risk factor for cardiovascular disease; although increased HDL level under high polyphenols and anthocyanins intake R
  • G Allele
    • G allele - higher PON1 expression (double the expression luciferase in hepatocytes) R

More Research

  • Serum PON1 concentration post-radiotherapy could be an efficient prognostic biomarker for efficacy of the RT. R