Modulatory Effect of Lifestyle-Related, Environmental and Genetic Factors on Paraoxonase-1 Activity: A Review

Abstract

Paraoxonase-1 (PON1) is a calcium-dependent, HDL-bound serum hydrolase active toward a wide variety of substrates. PON1 displays three types of activities, among which lactonase, paraoxonase, arylesterase and phosphotriesterase can be distinguished. Not only is this enzyme a major organophosphate compound detoxifier, but it is also an important constituent of the cellular antioxidant system and has anti-inflammatory and antiatherogenic functions. The concentration and activity of PON1 is highly variable among individuals, and these differences can be both of genetic origin and be a subject of epigenetic regulation. Owing to the fact that, in recent decades, the exposure of humans to an increasing number of different xenobiotics has been continuously rising, the issues concerning the role and activity of PON1 shall be reconsidered with particular attention to growing pharmaceuticals intake, dietary habits and environmental awareness. In the following manuscript, the current state of knowledge concerning the influence of certain modifiable and unmodifiable factors, including smoking, alcohol intake, gender, age and genotype variation on PON1 activity, along with pathways through which these could interfere with the enzyme’s protective functions, is presented and discussed. Since exposure to certain xenobiotics plays a key role in PON1 activity, the influence of organophosphates, heavy metals and several pharmaceutical agents is also specified.

The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis

“…Another mechanism is given by PON1’s ability to hydrolyze the macrophage plasma membrane surface of phospholipids when combined with HDL. This process drives n-lysophosphatidylcholine (LPC) production, which inhibits cholesterol fusion [ 45 ]. There have been studies on macrophages showing that PON1 reduces macrophage oxidative stress, indicating their role in oxidizing LDL [ 21 ].…”

“…Regarding the mechanism, it is believed that increased levels of diacylglycerol caused by high levels of glucose can cause PON1 gene transactivation via the PKC-mediated pathway [ 45 ]. The body’s response to insulin by GLUT4 expression is increased by PON1, but PON1 levels are independently reduced by type 2 diabetes, with a decreasing trend as diabetes progresses [ 63 , 64 ].…”

“…A study showed that chronic light alcohol intake raises PON1, while heavy drinking leads to lower PON1 expression. This explication comes from the fact that ethanol, by stimulating PKC, will raise PON1, but heavy consumption leads to PKC overexpression, which will inhibit PON1 [ 45 , 91 ]. Also, red wine, which contains antioxidant components, has led to higher HDL and lower LDL levels, mainly due the effect of the alcohol, as described, and the effect of resveratrol on PPAR-γ receptors [ 45 , 49 ].…”

“…This explication comes from the fact that ethanol, by stimulating PKC, will raise PON1, but heavy consumption leads to PKC overexpression, which will inhibit PON1 [ 45 , 91 ]. Also, red wine, which contains antioxidant components, has led to higher HDL and lower LDL levels, mainly due the effect of the alcohol, as described, and the effect of resveratrol on PPAR-γ receptors [ 45 , 49 ]. PON1 is also modulated by physical activity, with lower levels in people who are sedentary and obese.…”

“…Also, the transcription factor sterol regulatory element-binding protein 2 (SREBP-2), implicated in cholesterol synthesis, will bind with the PON1 promoter, linked with the MAPK cascade, and finally activate the PKC ( Figure 4 ). JNK can also upregulate PON1 by stopping the production of ROS [ 44 , 45 , 94 , 95 , 96 ]. Most polyphenols express the anti-inflammatory and antiatherogenic effect by increasing HDL, and the functional HDL is the one bound with PON1.…”