PON1 Genetics: Cardiovascular Disease & Detoxification Mechanisms

Author: Michael McEvoy

The PON1 genotype Q192R, risk allele ‘C’ is now considered a ‘high impact’ genotype that significantly increases cardiovascular disease risk. This article is an attempt to underscore the importance of PON1 and its associated antioxidant functions in the prevention of heart disease. We will cover some major literature on PON1, including genetics, the influence of environmental toxins, and importantly discuss potential therapeutic, nutrigenomics work-arounds for those who carry this high impact genotype.

Click the link at the bottom of this article if you’re interested in learning your PON1 genotype through your 23andme data.

PON1 Q192R is a gene located on chromosome 7. Also known as Paraoxonase, the gene produces a protein/enzyme that has unique functions. Two other related PON genes have been discovered, known as PON2 and PON3, respectively. PON’s are known for their ability to hydrolyze organophosphate pesticides, and consequently they were attributed as being as ‘arylesterase’ enzymes with the ability to hydrolyze carboxylic esters in a variety of chemicals. Thus, PON’s are bestowed with certain detoxification properties. By the late 1990’s it was known that polymorphisms in the PON1 Q192R gene significantly affects LDL oxidation, as well as the oxidation of cholesterol esters and phospholipids. Importantly, PON1 functions specifically in circulating HDL (high density lipoprotein), acting not only as a hydrolytic enzyme, but also as a crucial antioxidant to prevent and remove oxidized LDL (oxLDL) from circulation. These crucial functions have led to ongoing research into PON’s for their ability to significantly modify the risk of cardiovascular and other diseases. While this article is not going to cover the role and functions of PON2 and PON3, it should be pointed out that these other PON genes are being studied for potential roles in neurological diseases, cancer, diabetes, endometriosis and obesity.

PON1 (paraoxonase-1): Universal HDL Antioxidant

PON1 is synthesized in the liver, through the activation by the nuclear transcription factor PPAR-γ (Peroxisome proliferator-activated receptor gamma). PON1 enters circulation where it tightly binds to high density lipoprotein (HDL). HDL is a crucial transport vessel that acts to carry cholesterol, phospholipids, free fatty acids and triglycerides. Lipidomics research has identified that HDL particles contain and transport at least 25 different sub-fractions of lipids, as well as large numbers of apolipoproteins, enzymes, antioxidants such as glutathione, PON’s and glycoproteins (1). HDL possesses crucial antioxidant functions, which in turn acts to prevent the peroxidation of lipids, and importantly the formation of atherosclerotic-inducing oxLDL. PON1 is widely recognized as accounting for the majority of antioxidant functions to HDL (2).

The evolution of cardiovascular disease research has revealed that essential to the formation of atherosclerotic lesions is the presence and accumulation of oxLDL (oxidized low density lipoprotein). Unlike native LDL particles, oxLDL induces foam cell formation, a critical event in the pathophysiological process that drives atherogenesis. Accumulation of oxidized LDL induces toxic effects to cells and tissues (4-6). The ability to prevent and remove oxidized LDL from circulation is largely the role of HDL, and its PON1 proteinaceous antioxidant enzyme. While oxidized LDL is recognized as central to atherosclerosis, the driving factors that promote LDL oxidation are more controversial. It is proposed here that a perfect storm brews, which involves genetics, epigenetics, environmental insults (especially toxic metals, and pesticide exposure) and dietary factors (especially the toxic oxidation products of linoleic acid derived from vegetable oils). Compounding this perfect storm additionally involves the age-associated decline in HDL’s antioxidant function, which is directly caused by significant altercations in PON1’s critical antioxidant sulfhydryl group, Cys-284 (47).

Carriers of the PON1 Q192R ‘Q’ genotype (reported on genetic tests as TT or AA) carry a glutamine at position 191 on the protein, whereas carriers of the ‘R’ genotype (reported on genetic tests as CC or GG) carry an arginine substitution at position 191 on the protein. In 1998, a research team evaluated the differing effects of PON1 enzymatic activity, using the different isoforms (Q or R) and their abilities to inhibit LDL oxidation, through in vitro experiments. The Q isoform was able to reduce copper-mediated LDL oxidation by 58-61%, whereas the R genotype inhibited LDL oxidation by only 36-48%. In further experiments, this same team utilized the antioxidant glutathione peroxidase (Gpx) and incubated the different PON1 enzyme types to measure copper-mediated LDL oxidation, over 4 hours. Interestingly, it was found that the Q genotype was better at preventing LDL oxidation in the presence of glutathione, whereas the R genotype was better at inhibiting LDL oxidation after the process had already been initiated. This research pointed to the probability that the enzymatic, hydrolyzing abilities of PON1 is related to, but distinctly different from its antioxidant effect on LDL (3).

PON1 Q192R Genetics & Cardiovascular Disease Risk

Conflicting data has been reported regarding which PON1 Q192R genotype confers the risk for heart disease. Some studies report the TT genotype to be the risk, others report that GG is the risk. An extensive meta analysis and systematic review conducted by Ashiq and Ashiq published in 2021 began by analyzing 365 published studies on PON1 genetics and CAD risk, eventually whittling it down to 10 studies. Their conclusions are that the G genotype of PON1 Q192R (sometimes reported as C), is a significant risk factor for coronary artery disease (11). This same genotype was identified in the previously referenced in vitro assay from 1998 for having a reduced ability to prevent LDL oxidation (3). For risk of coronary artery disease, PON1 Q192R GG homozygote (sometimes reported as CC) appears to be the risk genotype.

PON1: Its Free Cysteine-284 Bestows Its Antioxidant & Anti-Atherogenic Function

The amino acid cysteine is one of the most conserved and least common amino acids in biology. When cysteine is bound with other amino acids, it forms matrices and bridges, which perform crucial roles in the dynamic, structural function of cells and proteins. When cysteine residues are ‘free’, they can actively participate in the yin/yang dance of oxidation and reduction, known as redox. Cysteine is a sulfhydryl amino acid. That is, in chemical terms, a sulfhydryl is also known as a thiol. It contains a sulfur atom bound to hydrogen, and a side chain that can be either a hydrogen or a carbon. Hence the chemical structure of a sulfhydryl is: RSH. Free cysteines are found all throughout the biology, and particularly in certain enzymes or proteins that possess crucial functions in maintaining an optimal redox milieu (reduction/oxidation), while performing important antioxidant actions. For example, the most abundant plasma protein known as albumin, carries a single, free cysteine residue, known as cys34. The sulfhydryl group in here is critical for maintaining the redox and antioxidant function of albumin, and that of the blood plasma (12). With cys34 and albumin, the higher the oxidized to reduced albumin ratio (as measured by the oxidation of cys34), the greater degree of oxidative stress. The point here is that free cysteines are regulatory amino acids with respect to antioxidant functions, and that when these cysteines increasingly oxidize, there is a greater loss of reducing power, redox regulation, greater toxicity and free radical damage.

The previously referenced in vitro study by Aviram, et al from 1998 demonstrated that the arylesterase enzyme activities differed from their abilities to protect against LDL oxidation. This forgotten and overlooked finding may have led researchers to assume PON1’s arylesterase enzymatic effects and its antioxidant functions are the same. Unfortunately not a great deal of studies has yet to elucidate the effects of PON1’s free cysteine-284 residue, and what specifically occurs in its different isoelectric oxidation states. However, like other free cysteines in biology (such as albumin’s cys34), they will undergo electron donation and in the process, themselves become oxidized, leading to the formation of sulfenic acids. This reaction is fortunately reversible with the right reducing, electron donor. However, during increased oxidative stress conditions, sulfonic and sulfinic acids can form from these oxidative reactions, leading to irreversible oxidation. If more free cysteine-284 oxidizes than can be reduced, PON1 could under the right conditions, easily lose its ability to function as an antioxidant. This in turn would lead to the Cys-284 residue becoming cysteinylated, and one would expect greater oxLDL and other lipid peroxidative species.

Cardiovascular Toxins: Mercury (Hg) & Lead (Pb) Inhibit PON1 Activity

To date, a very limited number of studies have been conducted to evaluate the effect of toxic metals on the function of PON1’s free cysteine residue. However it has been reported that several toxic metals may bind, interact and under certain conditions inactivate PON1’s active cysteine residue (49). Observational studies in humans support inhibitory effects of toxic elements on PON1.

Methylmercury is an increasingly common heavy metal toxin that is associated with cardiovascular disease risk. The most common source of methylmercury is from fish. A large scale study investigated the relationship between blood methylmercury concentrations, PON1 activity, omega 3 fatty acid content of red cells and selenium levels, among a population of 896 inuit. Increased methylmercury was associated with lower PON1 activity, and this effect was modified by higher selenium levels. In this study, PON1 genotypes were not found to be associated with blood mercury levels (41).

A study investigating the relationship between blood mercury levels, PON1 activity and PON1 genotype was conducted involving 881 adults living in the Cree Bay of Canada. No association was found with the PON1 Q192R genotype and blood mercury levels. However a statistically significant, inverse association was found among homozygotes with the PON1 -108T allele (rs705379). In other words, those homozygous with the risk allele for PON1 -108T had lower PON1 levels and higher blood mercury levels (42).

The toxic element lead (Pb) is a well established heavy metal element that exerts numerous toxic effects on the cardiovascular system, and lead toxicity is a known risk factor for cardiovascular disease. A study investigated the relationship between Pb blood levels, PON1 levels and PON1 genotype, among 597 workers who were employed in a lead-acid battery factory and recycling facility. Increased blood lead (Pb) levels were significantly associated with lower PON1 levels. Of 3 PON1 genetic variants analyzed (Q192R, -108T, L55M), homozygotes for the PON1 Q192R genotype (CC or GG) were more susceptible to the Pb-associated lower PON1 level effect. In other words, for homozygous carriers of the the primary, PON1 Q192R cardiovascular disease risk genotype (CC or GG), they were more likely to have lower PON1 levels when exposed to lead (43).

Linoleic Acid, a PUFA (Polyunsaturated omega 6 Fatty Acid) Abundant in Vegetable Oil Inhibits PON1 Activity

The linoleic acid hypothesis of cardiovascular disease has emerged as a significant driving risk factor, linking vegetable oil intake to heart disease risk. Briefly, the omega 6 polyunsaturated fatty acid, linoleic acid is hypothesized to be a driver of heart disease because of its ability to increase LDL oxidation, and increase foam cell formation. Significantly, oxidized linoleic acid and its unsaturated aldehyde metabolites are found abundantly in atherosclerotic plaques, and their degree of oxidation directly corresponds to the severity of atherosclerosis (6, 13). Of importance is that higher intake of linoleic acid is associated with causing reduced HDL, an increase in small, dense LDL particles, and an increase in triglycerides (6, 14).

A 2011 in vitro study evaluated the effect of linoleic acid hydroperoxide (a linoleic acid oxidation product found in atherosclerotic lesions) on PON1 activity. Critically, linoleic acid hydroperoxides interacts with PON1’s free cysteine-284 residue, inhibiting PON1’s lactonase enzyme function. A prolonged interaction with linoleic acid hydropersulfide resulted in an inhibitory effect on Cysteine-284 (15). Oxidized linoleic acid is toxic to endothelial function, and this research moves the needle one step further, by elucidating one important inhibitory mechanism on PON1.

Possible Ways to Increase or Improve PON1 Activity

A good deal of research has been published that provides evidence for dietary interventions, natural products and pharmacological agents’ abilities to increase PON1. What is currently lacking is how these therapeutic agents influence carriers of PON1 Q92R GG (or CC) genotypes. Additionally, some studies measure PON1 activity in plasma, others as a functional increase of PON1 in HDL particles, others as increased PON1 activity. Since there is no standardized testing, interpretation of data is challenging. It is generally thought that increases in HDL-C levels are synonymous with increased PON1 activity. This may not necessarily be the case for all genetic carriers of PON1 Q192R, CC/GG. See the list and my special commentary below.

A study involving 17 heart disease patients found that 1-2 grams of daily Niacin therapy (vitamin B-3) for 12 weeks significantly increased PON1 activity by 12-15%. Niacin was also shown in this study to significantly reduce triglycerides, reduce the inflammatory cytokine, IL-6, while significantly increasing HDL-C and apolipoprotein A-1 levels (16). Other evidence supports the use of niacin + daily walking. In a small study of 12 men with metabolic syndrome, 500-1,500mg of niacin (dosage scaled upto 1,500mg/daily) found that the combined effect of exercise plus niacin resulted in an 11.3% increase in PON1 concentrations, and a 6.1% increase in PON1 activity (18).
A small study investigating the effects of the long chain fatty alcohol, Policosanol (10mg daily) for 8 weeks was conducted on 25 individuals (young and middle aged). 10mg daily consumption of Policosanol resulted in a 17% increase of PON-1 activity, as measured inside of the subjects HDL particles. Additional increases in HDL-count ranged from 8-36%, decreases in triglycerides from 26-28%, serum CETP (cholesterol ester transferase protein) decreased between 21-36% (17). Other evidence for the increased PON1 levels and activity in HDL, was demonstrated in a small study of healthy Japanese subjects. 20mg of Policosanol increased PON1 levels in HDL-3 particles by 1.3 fold, compared to baseline, while no change occurred in the placebo group (19).
Red Grape Seed Extract contains proanthocyanidin polyphenolic antioxidants. This class of antioxidants is reportedly 50x stronger than Vitamins C and E. A total of 70 subjects with mild to moderate hyperlipidemia were studied and consumed either 200mg daily of RGSE, or a placebo for 8 weeks. RGSE increased PON1 from 112.7 to 117.2, a 4.5 point increase. The placebo group showed a 0.6 point decrease. The intervention group also experienced increases in HDL-C, decreases in LDL-C, decreases in triglycerides and total cholesterol, and increases in apoA1 (20).
Pomegranate juice contains potent antioxidants. Preliminary in vitro research found that pomegranate juice increases PON1 production in hepatocytes, partly by increasing the nuclear transcription factor PPAR-gamma (46). A notable study from 2003 involved 19 subjects with severe carotid artery medial stenosis, defined by a 70-90% stenosis. Subjects were divided into an intervention arm (n=10) and a placebo arm (n=9) that involved drinking 50ml of pomegranate juice daily (1.75 oz) for 1 year. After 1 year of drinking pomegranate juice, there was a 30% decrease in intimal medial thickness, but a 9% increase in the control group. PON1 arylesterase (enzymatic activity) increased 83% in the pomegranate group, along with a 90% reduction in LDL basal oxidative state, a 59% reduction in copper-ion-induced LDL oxidation, and a 19% decrease in antibodies measured against oxLDL, and a 21% reduction in systolic blood pressure. There was a 16% increase in triglycerides in the intervention group, but no other changes in blood lipids, coagulation, homocysteine or lipoprotein a (21).
EPA Fish Oil is comprised of Omega 3 Fatty Acids. 36 patients with diabetes mellitus were randomized to either 2,000mg of EPA fish oil, or placebo. EPA intake resulted in a 22-point ng/ml increase in circulating PON1 levels, and a 7-point U/l increase in PON1 activity. Additionally observed were significant increases in HDL and reductions in total cholesterol (29)
Statin drugs are known to increase paraoxonase and arylesterase enzyme activity, but not PON1 protein levels (22). Sub-group analysis has identified that statin drug use is associated with Alzheimer’s disease risk, and non-Alzheimer’s dementia (23). Statin use is associated with increased risk of hyperglycemia (24). A review of 14 studies identified statin use is associated with a 9-33% higher risk of new-onset diabetes mellitus (25). Statin use is significantly associated with Parkinson’s disease risk, especially lipophilic statins, among patients with elevated cholesterol (26). Statins have been proposed as mitochondrial toxins, as causative agents in arterial calcification, heart failure and atherosclerosis, through their inhibition of CoQ10, heme A, Vitamin K2 and selenoproteins, including glutathione peroxidase (27). It has been shown that high dosage and longterm statin use accelerates arterial calcification (28).
Light alcohol consumption increases PON1 activity, whereas heavy drinking inhibits it (50)

Drugs, Chemicals, Pesticide Substances That Lower PON1 Activity

Many cardiovascular disease drugs have been shown in in vitro studies to reduce PON1 activity. This includes: digoxin, metoprolol tartrate, verapamil, diltiazem, amiodarone, dobutamine, and methylprednisolone (7).
Rat studies have found that the flouroquinolone antibiotics Ciprofloxine and Levaquin inhibit PON1. One research study proposed PON1 inhibition by flouroquinolones as being possibly etiological in this drug’s association with cardiovascular complications (48)
Calcium-channel blocking, blood pressure-lowering drugs was shown to lower PON1 in vitro, as do Sulfonomides (8,9).
Margarine lowered PON1 activity by 6% (30).
Acrolein, an unsaturated aldehyde derived from a variety of sources, including smoking and high temperature cooked oils, inactivates PON1 in hemodialysis patients (39).
Notably, increased Linoleic acid hydroperoxide-derived carotid lesions are associated with lower PON1 and HDL-C levels in humans (40).
Organophosphate pesticides are chemical toxins with known suppressive effects on PON1 (45)
Extrapolating data from organophosphate pesticide studies reveals interesting findings, that the PON1 Q912R genotype QQ (AA/TT) is associated with the lowest arylesterase activity against the chemical parathion, whereas the RR (CC/GG) genotype has greater arylesterase activity against parathion (44). The findings are opposite what one would expect. To clarify, RR genotypes carry the greatest CVD risk, and greater susceptibility to reduced PON1 effects by toxic metals, but have stronger hydrolytic enzyme effects against chemical pesticides.

Unknown Promoters of PON1, But Top Candidates for Future Research

Berberine, a commonly used plant alkaloid for glucose control has been proposed as a potential promoter of PON1 due to its ability to affect other lipid-related markers. including S1P (sphingosine-1-phosphate), LCAT, cholesterol efflux, LDL and HDL (31). Preliminary in vitro research found berberine increases PON1 in liver cells (32). One possible, unknown caveat is that Berberine activates AMPK (which is attributed to it’s glucose-lowering properties). AMPK can inhibit PPAR-gamma, the transcription factor that activates PON1 in the liver.
Aged Garlic is now considered a reference nutraceutical for significantly attenuating cardiovascular disease risk factors in humans. For example, aged garlic significantly attenuates arterial calcification, among those with an elevated CAC risk (33). Aged garlic can significantly increase HDL-C in humans (34), significantly increase apolipoprotein a1 (the primary protein component of HDL), significantly reduce markers of endothelial inflammation: ICAM-1, VCAM-1, MCP-1 (35), inhibits foam cell formation in vitro (36), and therefore should be studied for increasing PON1. Future research should be aimed specifically at studying the effect of aged garlic’s sulfur compounds on interacting with PON1’s Cys-284 residue.
NAC (n-acetyl cysteine) is a precursor to glutathione. NAC was shown to break the cysteinlyated disulfide bond of serum albumin’s cys34 residue, acting as an extracellular antioxidant (37). Similarly, researchers should study how NAC interacts with PON1’s Cys-284 residue during oxidative stress conditions. A combination of Propolis and NAC was trialed in patients with acute respiratory infections, and was found to slightly increase PON1 and HDL levels (38). It was shown in an ex vivo study, from blood samples derived from hemodialysis patients that NAC rescued acrolein-induced PON1 inactivation (39).

Summary

Coronary artery disease is a complex, multifaceted inflammatory condition involving a variety of converging factors.
Homozygotes of the PON1 Q192R Genotype R (CC/GG) are at increased risk for coronary artery disease, due to a reduced ability to prevent and/or remove oxidized LDL.
A variety of toxic metals, pesticides, certain pharmaceuticals, the omega 6 vegetable oil linoleic acid, as well as aging are known to further inhibit or reduce PON1 function and/or enzyme activities, which may compound heart disease risk for homozygotes.
A limited number of natural products have been trialed as efficacious for improving PON1 activities, while providing clear cardiovascular benefits.

If you’re interested in knowing your PON1 genetics, use our Nutrigenomics report to analyze your raw data from 23andme or AncestryDNA.

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Category: FeaturedBy Michael E. McEvoy February 19, 2024 Leave a comment

Author: Michael E. McEvoy

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PON1 Genetics: Cardiovascular Disease & Detoxification Mechanisms

PON1 (paraoxonase-1): Universal HDL Antioxidant

PON1 Q192R Genetics & Cardiovascular Disease Risk

PON1: Its Free Cysteine-284 Bestows Its Antioxidant & Anti-Atherogenic Function

Cardiovascular Toxins: Mercury (Hg) & Lead (Pb) Inhibit PON1 Activity

Linoleic Acid, a PUFA (Polyunsaturated omega 6 Fatty Acid) Abundant in Vegetable Oil Inhibits PON1 Activity

Possible Ways to Increase or Improve PON1 Activity

Drugs, Chemicals, Pesticide Substances That Lower PON1 Activity

Unknown Promoters of PON1, But Top Candidates for Future Research

Summary

Author: Michael E. McEvoy

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