The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin

Davies, Holly G.; Richter, Rebecca J.; Keifer, Matthew; Broomfield, Clarence A.; Sowalla, Jason; Furlong, Clement E.

doi:10.1038/ng1196-334

Cited by 563 publications

(410 citation statements)

References 17 publications

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“…This finding is in agreement with the other studies that there was at least a 13-fold variation in PON1 activity among individuals with the same genotype (Humbert et al 1993;Davies et al 1996;Richter and Furlong 1999). It is possible that not only the serum PON1 activity is influenced by the PON1 polymorphisms but also by the other factors.…”

Section: Discussionsupporting

confidence: 93%

“…The PON1 Q192R polymorphism has been shown to be responsible for the substratedependent difference in the kinetics of hydrolysis by each PON1 192 isoform (Adkin et al 1993;Humbert et al 1993). The R alloenzyme hydrolyses paraoxon more rapidly than the Q alloenzyme while the Q alloenzyme hydrolyses diazoxon, soman and sarin more rapidly than the R alloenzyme (Li et al 2000;Davies et al 1996). Of the PON1 192 alloenzymes, the Q alloenzyme has proved to be more efficient in protecting LDL from oxidation (Aviram et al 1998b;Mackness et al 1997aMackness et al , 1997b.…”

Section: Introductionmentioning

confidence: 99%

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Paraoxonase 1 status in the Thai population

et al. 2005

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Human serum paraoxonase 1 (PON1), a highdensity lipoprotein (HDL)-associated enzyme, has been shown to reduce the oxidation of low-density lipoprotein (LDL) and HDL by degrading lipid peroxides. This property of PON1 accounts for its ability to protect against atherosclerosis. In this study, we identified four polymorphisms in both the coding (L55M and Q192R) and regulatory regions (T-108C and G-909C) of the human PON1 gene in 202 healthy Thai individuals and investigated the influence of these polymorphisms on serum PON1 activity towards three substrates, namely, paraoxon, phenylacetate and diazoxon. The PON1 L55M, Q192R and G-909C polymorphisms significantly affected the variation in serum PON1 activity towards paraoxon. Serum PON1 activity towards paraoxon was significantly different among the genotype groups, as follows: 55LL > 55LM/55MM, 192RR > 192QR > 192QQ and À909CC > À909CG > À909GG. The PON1 Q192R and G-909C polymorphisms also influenced the variation in serum PON1 activity towards diazoxon but in the opposite direction to the activity towards paraoxon. Only the PON1 L55M polymorphism was associated with significant variation in serum PON1 activity towards phenylacetate while the PON1 T-108C polymorphism had no significant effect on serum PON1 activity towards any substrate. We also found linkage disequilibrium among the polymorphic sites, including Q192R versus L55M, Q192R versus T-108C and Q192R versus G-909C. Serum PON1 activity towards both paraoxon and phenylacetate, but not diazoxon, was positively correlated with HDL cholesterol (HDL-C) and apo AI concentrations. None of the PON1 polymorphisms significantly affected serum lipid, lipoprotein or apolipoprotein concentrations. Our findings suggest that the physiological relevance of the PON1 polymorphisms is that they are associated with significant differences in serum PON1 activity, and the impact of PON1 polymorphisms on this activity is substrate-dependent.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Paraoxonase 1 status in the Thai population

et al. 2005

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“…There was a mean 4.4% variation between assays for these 29 samples. The assay results for the three substrates permitted separation of activity levels, providing determination of the inferred genotype of each subject's PON1 (Furlong et al, 1989;Davies et al, 1996;Richter and Furlong, 1999). PON1 inferred genotypes were determined from two-dimensional enzyme plots showing the rates of hydrolysis of chlorpyrifos oxon and of diazoxon plotted against the rates of hydrolysis of paraoxon for each subject's plasma.…”

Section: Pon1 Inferred Genotype and Chlorpyrifosoxonase Activitymentioning

confidence: 99%

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

Albers

Garabrant

Berent

et al. 2009

J Expo Sci Environ Epidemiol

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Chlorpyrifos is an organophosphorus (OP) anticholinesterase insecticide. Paraoxonase (PON1) is an enzyme found in liver and plasma that hydrolyzes a number of OP compounds. PON1 polymorphisms include a glutamine (Q)/arginine (R) substitution at position 192 (PON1 Q192R ) that affects hydrolysis of OP substrates, with the PON1 192Q allotype hydrolyzing chlorpyrifos oxon less efficiently than the PON1 192R allotype, a variation potentially important in determining susceptibility to chlorpyrifos. We studied 53 chlorpyrifos workers and 60 referents during 1 year and estimated chlorpyrifos exposure using industrial hygiene and employment records and excretion of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCP). Plasma butyrylcholinesterase (BuChE) activity, which may by inhibited by chlorpyrifos exposure, was measured monthly. In addition, plasma samples were assayed for paraoxonase (PONase), diazoxonase (DZOase), and chlorpyrifosoxonase (CPOase) activity to determine PON1 status (inferred genotypes and their functional activity). Linear regression analyses modeled BuChE activity as a function of chlorpyrifos exposure and covariates. We postulated that the level of CPOase activity and the inferred PON1 192 genotype (together reflecting PON1 status) would differ between groups and that PON1 status would modify the models of chlorpyrifos exposure on BuChE activity. Chlorpyrifos workers and referents had a 100-fold difference in cumulative chlorpyrifos exposure. Contrary to our hypotheses, mean CPOase activity was similar in both groups (P ¼ 0.58) and PON1 192Q showed a slight overrepresentation, not an underrepresentation, in the chlorpyrifos group compared with referents (PON1 192QQ , 51% chlorpyrifos, 40% referent; PON 192QR , 43% chlorpyrifos, 40% referent; PON 192RR , 6% chlorpyrifos, 20% referent, P ¼ 0.08). In our models, BuChE activity was significantly inversely associated with measures of interim chlorpyrifos exposure, but the biological effects of chlorpyrifos exposure on BuChE activity were not modified by PON1 inferred genotype or CPOase activity.

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“…Serum PON1 activity is influenced by environmental and genetic factors and varies among individuals in all populations. These variations in PON1 activity are mainly related to the expression of two polymorphisms located in the coding regions of the PON1 gene; Q192R (Q: glutamine, R: arginine) and L55M (L: leucine, M: methionine) [1,9,13,17,23,27]. Subsequent studies on polymorphisms contained in the promoter region of the PON1 locus have shown that the polymorphism located in the promoter region T(-107)C has a dominant effect on PON1 gene expression and enzymatic activity [5,14,22].…”

Section: Introductionmentioning

confidence: 99%

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Nagila

Permpongpaiboon

Tantrarongroj

et al. 2009

Pharmacological Reports

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Abstract:It has been proposed that paraoxonase1 (PON1), a high density lipoprotein (HDL)-associated esterase/lactonase, has antiatherosclerotic properties. The activity of PON1 is influenced by PON1 polymorphisms. However, the influence of PON1 polymorphisms on PON1 activity and oxidative stress in response to lipid-lowering drugs remains poorly understood. The objective of the present study was to investigate the effects of atorvastatin on PON1 activity and oxidative status. The influence of PON1 polymorphisms on PON1 activity and oxidative status in response to atorvastatin treatment was also evaluated. In total, 22 hypercholesterolemic patients were treated with atorvastatin at a dose of 10 mg/day for 3 months. Lipid profile, lipid oxidation markers (malondialdehyde (MDA), conjugated diene (CD), total peroxides (TP)), total antioxidant substance (TAS), oxidative stress index (OSI), and paraoxonase1 activity were determined before and after treatment. L55M, Q192R, and T(-107)C PON1 polymorphisms were also determined. Atorvastatin treatment significantly reduced the levels of total cholesterol (24.5%), low density lipoprotein (LDL) cholesterol (25.4%), triglycerides (24.4%), CD (4.4%), MDA (15.2%), TP (13.0%) and OSI (24.0%), and significantly increased the levels of TAS (27.3%), and PON1 activity (14.0%). Interestingly, the increase in PON1 activity and the reduction in oxidative stress in response to atorvastatin were influenced only by the PON1 T-107C polymorphism. Atorvastatin treatment improved the lipid profile, lipid oxidation, and oxidative/antioxidative status markers including the activity of PON1 towards paraoxon. These beneficial effects may be attributed to the antioxidant properties of statins and the increase in PON1 activity. The increase in PON1 activity was enhanced by the PON1 T-107C polymorphism.

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The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin

Cited by 563 publications

References 17 publications

Paraoxonase 1 status in the Thai population

Paraoxonase 1 status in the Thai population

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

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