The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism | SpringerLink
Figure 4. Discussion Ocular damage due to organophosphate pesticides exposure was studied by the US environmental protection agency subsequent to reports from India and Japan  — . Supporting Information. Figure S1.
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The Paraoxonases Their Role In Disease Development And Xenobiotic Metabolism
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Toxicol — Dementi B Ocular effects of organophosphates: a historical perspective of Saku disease. Pharmacol — Lancet 1: Verma RS, Srivastava N Chlorpyrifos induced alterations in levels of thiobarbituric acid reactive substances and glutathione in rat brain.
Indian J Exp Biol —7. Figure 1 point to the metabolisms of the some organophosphate by PON1. On the other hand this enzyme contain a histidine aminoacid at position , , and and cysteine at the 42, and position, in active site. This histidine is essential for esterase activity and cysteine is essential for hydrolase activity, thus zinc or nickel may bind to histidine. Other metals e. PON1 variants may represent a biomarker for identifying individuals susceptible to organophosphorus neurotoxicity leading to neurodegeneration and PD . On the other hand this enzyme has been shown to be inactivated by oxidative stress and many antioxidative nutrients .
Studies have shown PON1 polymorphisms generated variable susceptibility to different diseases. The PON1 polymorphisms affect the catalytic abilities of this enzyme. The R allele at position hydrolyzes paraoxon faster than the Q allele but hydrolyzes diazoxon slowly. Then, homozygotes for the B allele are poor metabolizer of organophosphate such as diazoxon, soman and sarin. The plasma concentration of the enzyme in M allele at position 54 is lower from L54 allele. In other words, plasma of homozygous individuals for the wild-type Leu-allele of the rs polymorphism has higher PON1 mRNA, protein and higher PON1 activity than homozygous for Met-allele carriers, while heterozygous carriers have intermediate mRNA, protein levels [48,55].
Several previous studies showed the association of one or both of these polymorphisms with PD.
The Paraoxonases Their Role In Disease Development And Xenobiotic Metabolism
Akhmedova et al. A further evidence for this association was shown in a Swedish case—control study. However, some studies indicated there is no an association between PON1 polymorphisms an Parkinson's disease . The aim of the present study includes investigation of both the M54L and the RQ allele, genotype and haplotype distribution in PD patients and healthy subjects.
In addition to these polymorphisms, some investigators have recently detected polymorphic mutations in the promoter region of PON1 gene, in particular, the T C promoter polymorphism has been shown to affect PON1 gene expression and enzymatic activity . PON1 activity has been shown to be regulated both genetically and by post translational modifications [59,60]. PON1 diurnal activity is quite constant. Thus, the decrease in PON1 activity may contribute to the increased susceptibility of HDL to oxidation; decreased in detoxification of organophosphates because of aging and oxidative damage.
In newborns, PON1 activity until 6 months age is very low, suggesting that newborns can be significantly more sensitive to poisoning by pesticide than adults . In rats, no differences were found in plasma and liver PON1 activity between 3- and month-old animals . Recent investigations have reported a progressive decrease in PON1 activity in elderly humans. More over many other factors can affect the PON1 activity and concentration. Some factors such as Dietary cholesterol, alcohol use, and vitamin C associate with an increase in AREase activity.
And others like iron and folic acid can decrease AREase activity . The effects of various dietary fats on PON1 status have been evaluated in rats. Interestingly, PON1 activity in mice and humans can be increases with feed Oleic acid [64,65], others studies shows that Aspirin use associated with high serum levels of paraoxonase activity  and synthesis of the PON1 protein as well as activity reduced by glycation of this enzyme .
Experimental evidence showed that serum activity in healthy subjects is directly related to protein concentration. Moreover, heterozygous AB individuals have an intermediate level.
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It was shown the 55 polymorphism also affected the PON1 concentration. However it could not be found such effects in healthy population . Considering the role of PON1 in PD, the concentration and activity of this enzyme can be different in Parkinson's patients and healthy subjects. PON1 activity can be regulated genetically and environmentally . This protection of PON1 is most probably related to the hydrolyzing of some activated lipids  and other lipid peroxide products  which are produced during the acute phase response.
Regarding the roles of these factors, activity of PON1 can be changed in different inflammatory and infectious diseases. PON1 activity has been observed decrease in the serum of patients diagnosed with chronic hepatitis , rheumatoid arthritis , multiple sclerosis , diabetes mellitus , atherosclerosis, Alzheimer dementia and cancers . These types are the most common cancers in developed countries.
The serum paraoxonase eliminates carcinogenic radicals [81,82]. PON1 activity in patients who have survived a myocardial infarction was reported to be lower [85,86]. The L55M polymorphism, make lowers paraoxonase activity by decreasing the amount of this enzyme present in blood. It was shown that increased amount of ROS in plasma may be a sign of rheumatoid arthritis. Baskol et al. Studies found that PON1 activity was lower in patients with cirrhosis than in those with hepatitis. Alterations of the structure and circulatory levels of HDL was attributed to the hepatic LCAT activity which is frequently affect by chronic liver diseases [92,93].