Dataset Information

Paraoxonase (PON1 and PON3) Polymorphisms: Impact on Liver Expression and Atorvastatin-Lactone Hydrolysis.

ABSTRACT: Atorvastatin ?-lactone, a major, pharmacologically inactive metabolite, has been associated with toxicity. In a previous study we showed that polymorphisms of UGT1A3 influence atorvastatin ?-lactone formation. Here we investigated the reverse reaction, atorvastatin ?-lactone hydrolysis, in a human liver bank. Screening of microarray data revealed paraoxonases PON1 and PON3 among 17 candidate esterases. Microsomal ?-lactone hydrolysis was significantly correlated to PON1 and PON3 protein (r(s)?=?0.60; r(s)?=?0.62, respectively; P??C, -832G?>?A, -1741G?>?A) and a tightly linked group of PON3 polymorphisms (-4984A?>?G, -4105G?>?A, -1091A?>?G, -746C?>?T, and F21F) to be associated with changes in atorvastatin ?-lactone hydrolysis and expression of PON1 but not PON3. However, carriers of the common PON1 polymorphisms L55M or Q192R showed no difference in ?-lactone hydrolysis or PON expression. Haplotype analysis revealed decreased ?-lactone hydrolysis in carriers of the most common haplotype *1 compared to carriers of haplotypes *2, *3, *4, and *7. Analysis of non-genetic factors showed association of hepatocellular and cholangiocellular carcinoma with decreased PON1 and PON3 expression, respectively. Increased C-reactive protein and ?-glutamyl transferase levels were associated with decreased protein expression of both enzymes, and increased bilirubin levels, cholestasis, and presurgical exposure to omeprazole or pantoprazole were related to decreased PON3 protein. In conclusion, PON-locus polymorphisms affect PON1 expression whereas non-genetic factors have an effect on PON1 and PON3 expression. This may influence response to therapy or adverse events in statin treatment.

SUBMITTER: Riedmaier S

PROVIDER: S-EPMC3147178 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Paraoxonase (PON1 and PON3) Polymorphisms: Impact on Liver Expression and Atorvastatin-Lactone Hydrolysis.

Riedmaier Stephan S Klein Kathrin K Winter Stefan S Hofmann Ute U Schwab Matthias M Zanger Ulrich M UM

Frontiers in pharmacology 20110727

Atorvastatin δ-lactone, a major, pharmacologically inactive metabolite, has been associated with toxicity. In a previous study we showed that polymorphisms of UGT1A3 influence atorvastatin δ-lactone formation. Here we investigated the reverse reaction, atorvastatin δ-lactone hydrolysis, in a human liver bank. Screening of microarray data revealed paraoxonases PON1 and PON3 among 17 candidate esterases. Microsomal δ-lactone hydrolysis was significantly correlated to PON1 and PON3 protein (r(s) = ...[more]

PMID: 21852972

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Project description:ContextParaoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated.ObjectiveTo investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans.Design, setting, and participantsThe association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity.Main outcome measuresRelationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD.ResultsThe PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P < .001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1-5.5; P < .001) and for arylesterase, 2.9 (95% CI, 1.8-4.7; P < .001) and remained independent in multivariate analysis.ConclusionThis study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.

Dataset Information

Paraoxonase (PON1 and PON3) Polymorphisms: Impact on Liver Expression and Atorvastatin-Lactone Hydrolysis.

Publications

Paraoxonase (PON1 and PON3) Polymorphisms: Impact on Liver Expression and Atorvastatin-Lactone Hydrolysis.

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