Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs)
Tom J J Schirris1,2, Tina Ritschel3, Albert Bilos1
1Department of Pharmacology and Toxicology, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.
Molecular Pharmaceutics
|September 29, 2015
Summary
Statins can cause muscle problems, with lactone forms being more toxic. Specific uridine 5'-diphospho-glucuronosyltransferases (UGTs) like UGT1A3 are key to this conversion, offering insights into personalized statin therapy.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Cardiovascular Pharmacology
Background:
- Statins are widely prescribed for cardiovascular event risk reduction.
- Statin-induced myopathies are common adverse effects, potentially linked to toxic lactone metabolites.
- The specific uridine 5 -diphospho-glucuronosyltransferase (UGT) enzymes responsible for statin lactonization remain incompletely characterized.
Purpose of the Study:
- To systematically characterize the subtype specificity and kinetics of statin lactonization by UGT enzymes.
- To identify UGTs involved in the formation of potentially toxic statin lactone metabolites.
- To explore the implications of UGT polymorphisms for personalized statin therapy and safety.
Main Methods:
- In vitro assessment of lactonization activity for six clinically relevant statins across various UGT subtypes.
- Kinetic analysis to determine the relative conversion rates of statins by identified UGTs.
- In silico molecular modeling to identify potential statin interaction sites within UGT binding pockets.
Main Results:
- UGT1A1, UGT1A3, and UGT2B7 were identified as the primary enzymes mediating statin lactonization.
- UGT1A3 exhibited the highest lactonization capacity, with significant variations in statin conversion rates (pitavastatin > atorvastatin > cerivastatin > lovastatin > rosuvastatin; simvastatin not converted).
- In silico modeling suggested specific interaction regions within UGTs for statin binding.
Conclusions:
- UGT1A3 plays a crucial role in the lactonization of several statins, influencing their metabolic activation to potentially toxic forms.
- Genetic variations (polymorphisms) in UGT1A1, UGT1A3, and UGT2B7 may contribute to the variability in statin-induced myopathies.
- Understanding these UGT-mediated metabolic pathways offers a potential avenue for personalizing statin therapy to enhance patient safety.
Keywords:
HMG-CoA reductase inhibitorsUGT homology modelsacyl-coenzyme Aglucuronidationlactonizationstatin-induced myopathystatinsuridine 5′-diphospho-glucuronosyltransferase (UGT)More Related Videos
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