Paraoxonase (PON1) Phenotype Is a Better Predictor of Vascular Disease Than Is PON1 ₁₉₂ or PON1 ₅₅ Genotype

Abstract

Abstract-The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 ageand race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had Ͼ80% carotid stenosis, and the 106 controls had Ͻ15%. [15][16][17] The cardioprotective role of HDL, the inhibition or reduction of atherogenic LDL oxidation, appears to be, in large part, a function of PON1, which is associated with HDL. 18 -22 PON1 metabolizes mildly oxidized phospholipids, presumably by eliminating hydroperoxy derivatives of unsaturated fatty acids. 20 Thus, the PON1-CVD association is expected to result from the role of PON1 in the metabolism of bioactive lipid molecules and protection against damage due to oxidized LDL.PON1 hydrolyzes a variety of substrates, including the toxic components of the pesticides parathion, chlorpyrifos, and diazinon; aryl esters, such as phenyl acetate; and the nerve agents soman and sarin. There is 10-to 40-fold interindividual variability in rates of paraoxon hydrolysis. 23 The PON1 192Q allele has the higher rate of in vitro hydrolysis of diazoxon, sarin, and soman, 24 whereas the PON1 192R allele has higher activity for the hydrolysis of paraoxon and chlorpyrifos oxon. 24,25 These rates of substrate hydrolysis are quite variable within PON1 genotypes (at least 13-fold) and represent phenotypes that can add information about PON1 status beyond genotyping alone. 24 Paraoxon hydrolysis activity is lost in the plasma of the PON1 knockout mouse, and these mice are more susceptible to atherosclerosis. 26 We compared the PON1 192 and PON1 55 genotypes with PON1 rates of hydrolysis of paraoxon (POase activity) and diazoxon (DZOase activity) for their predictiveness in vascular disease of the carotid arteries. These 2 substrates were chosen because, relative to the other isoform, the PON1 192Q isoform has a higher DZOase activity and the PON1 192R isoform has a higher POase activity in the in vitro assays. The resulting 2D plot (Figure 1) allows an accurate inference of PON1 192 genotype, in addition to providing PON1 phenotype information. 27 Methods Sample

Paraoxonase 1 status in the Thai population

“…Thus, it is likely that paraoxon and phenylacetate seemed to be better surrogate substrates than diazoxon for measuring PON1 activity. Jarvik et al (2000) found that the PON1 activity towards diazoxon was more predictive of vascular disease status than was the PON1 activity towards paraoxon in marginal analysis. However, in the only prospective study published so far, paraoxon but not diazoxon hydrolysis was an independent risk factor for CHD events (Mackness et al 2003).…”

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

“…These standards showed less than 8% variability between independent assays. An additional 26 samples from a previously determined PON1 status frequency distribution of known phenotypes and genotypes (Jarvik et al, 2000) were included as additional standards for CPOase assays. There was a mean 4.4% variation between assays for these 29 samples.…”

Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene–environment interactions

“…57,58 Unfortunately, paraoxonase activity is calcium dependent and cannot be measured in the plateletrich plasma we have collected from our entire sample. We have thus begun assessing paraoxonase, diazoxonase, and arylesterase activity in all 217 serum samples currently available from the AGRE collection, 30 including 40 families with one or more autistic patients and their first-degree relatives.…”