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 (rs = 0.60; rs = 0.62, respectively; P < 0.0001). PON1 and PON3 were strongly correlated to each other (rs = 0.60) but PON1 was shown to be more extensively glycosylated than PON3. In addition a novel splice-variant of PON3 was identified. Genotyping of 40 polymorphisms within the PON-locus identified PON1 promoter polymorphisms (−108T > 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.
Highlights
Enzymatic compared to spontaneous hydrolysis, the latter of which was assessed by identical incubation with heat-inactivated protein fractions, was found to be 1.3-fold higher for lovastatin-lactone and 3.8-fold higher for atorvastatin-lactone in a pooled microsomal fraction
Establishing the atorvastatin-lactone hydrolysis assay, we could show that the activity was increased by approximately 20% by adding 1 mM CaCl2, these reactions are not depending on co-substrates
paraoxonase 1 (PON1) and paraoxonase 3 (PON3) were identified as the major enzymes for hydrolysis of atorvastatin-lactone in human liver
Summary
Severe adverse events are rare, but hepatotoxicity, myopathy, and rhabdomyolysis are well known. A comprehensive explanation for the development of the described adverse events has not yet been found. On the other hand it was shown that highly metabolized statins like atorvastatin were associated with the highest risk for adverse events (Law and Rudnicka, 2006; Silva et al, 2006). This is further emphasized by reports of increased numbers of adverse events when statins are co-administered with known inhibitors of statin metabolizing enzymes. After the death of several people caused by this co-medication, it was decided to withdraw cerivastatin from the market
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have