Wordprocessing

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

Abstract:

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) = 0.60; r(s) = 0.62, respectively; P < 0.0001).> 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 δ-lactone hydrolysis and expression of PON1 but not PON3. However, carriers of the common PON1 polymorphisms L55M or Q192R showed no difference in δ-lactone hydrolysis or PON expression. Haplotype analysis revealed decreased δ-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 γ-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.

21852972

Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes

Front Pharmacol
Front Pharmacol 2: 41
27th Jul 2011

Stephan Riedmaier, Kathrin Klein, Stefan Winter, Ute Hofmann, Matthias Schwab, Ulrich M Zanger

help Authors

[Kathrin Klein] [Ute Hofmann] [Matthias Schwab] [Ulrich Zanger]

help Attributions

None

help Scales


Cell
Views: 2281
  • Created: 27th Jun 2012 at 16:05
  • Last updated: 24th Oct 2013 at 16:18

Related items

Ajax-loader-large

Log in / Register

Need an account?
Sign up

Forgotten password?

Front Page

Virtual Liver Network

(v.0.22.0)

Related Projects and friends


Imprint Taverna workflow workbench myExperiment JWS Online ISATAB myGrid Sabio-RK BioPortal Semantic SBML

Powered by:

Ror-logo-32

Icons:
Silk icons 1.3
Crystal Clear icons