The mechanism underlying the increased PON
The mechanism underlying the increased PON1 levels found in greenhouse workers may be accounted for by an increased protein IC-87114 following pesticide interaction with different nuclear receptors as also occurs with other chemicals, such as polyphenols and statins . A number of nuclear receptors have been identified within the PON1 promoter region, including pregnane X receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). PXR is an important component of the body\'s adaptive defense mechanism against toxic substances that can bind numerous chemicals belonging to structurally unrelated groups of molecules. Pesticides such as organochlorines, pyrethroids, triazoles and OPs insecticides are PXR ligands , , . PXR activation has been suggested to increase promoter expression of the antioxidant PON1 as an effort to counter pesticide-induced oxidative stress . Moreover, certain pesticides and herbicides have been shown to activate PPARα in mice . Since activation of PPARα results in PON1 expression, it is plausible that exposure to some pesticides (or their metabolites) might lead to increased expression of PON1 . Activation of PPARγ is also associated with increased PON1 expression, thus playing an important role in counteracting oxidative stress . However, there is limited evidence so far indicating that pesticides may activate PPARγ , . PON1 has been reported to form a network with related proteins, including AChE and BChE . Since genes encoding for PON1 and AChE are located in close proximity on chromosome 7q21-22, changes in these adjacent genes can impact each other\'s expression. An inverse relationship has been reported between plasma PON1 and AChE enzyme activities, indicating that PON1 can protect plasma AChE inactivation by reducing oxidative stress . In line with this, the reduced AChE levels observed in this study for greenhouse workers may have led to an increase in PON1 expression to compensate for the lower AChE activity. On the other hand, PON1 also form a network with BuChE as both proteins are two major bioscavengers involved in the regulation of inflammation, oxidative stress and lipid metabolism , . In relation to the contribution of genetic polymorphisms on the enzyme levels, PON1 Q192R polymorphism affected all PON1 activities studied, as carriers of 192RR genotype exhibited higher POase activity but lower AREase, DZOase and DHCase. The significant differences seen for AREase across PON1 genotypes in different studies, including ours, opposes the prevailing belief that AREase is unaffected by genotype and cast doubts on whether this activity can accurately estimate serum levels of PON1 protein. Our findings are partially in line with ; who found that promoter region polymorphisms were highly associated with AREase, lactonase, and DZOase, whereas the functional variant PON1 Q192R exhibited the greatest effect on POase and was less associated with other substrate-specific activities. In our study, the 192QQ genotype showed higher lactonase activity than the 192RR genotype, which supports McDaniel et al. results (2014) . As lactones are likely the native substrates for PON1, lactonase activity may be a relevant marker of PON1 phenotype, particularly for studies related to oxidative stress rather than OPs pesticide exposure . Our findings indicate that neither PON1 192 nor PON1 55 polymorphisms have a significant effect on plasma BuChE as also reported ; however, the PON1 192RR genotype was associated with lower AChE activity, with a finding consistent with results from a previous study . Regarding BCHE gene polymorphisms, carriers of the BCHE K/K genotype had a BeChE activity 25% lower than homozygous for the usual genotype, roughly close to the 30% reduction reported elsewhere . However, a near significant difference of only 15% was observed for BuChE. The BCHE K/K genotype was also associated with higher AChE activity (36% greater than the usual genotype), likely suggesting a feedback mechanism or a kind of counter-regulation to compensate for a lower plasma cholinesterase. In contrast, the BCHE-A variant failed to be associated with any of the cholinesterase activities assayed (although heterozygous subjects showed a non-significant decrease in BuChE as compared to carriers of the usual genotype). The BCHE-A variant only showed a positive association with DZOase and lactonase, a finding that warrants further research.