title: Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs).
abstract: Statins are cholesterol-lowering drugs that have proven to be effective in lowering the risk of major cardiovascular events. Although well tolerated, statin-induced myopathies are the most common side effects. Compared to their pharmacologically active acid form, statin lactones are more potent inducers of toxicity. They can be formed by glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), but a systematic characterization of subtype specificity and kinetics of lactonization is lacking. Here, we demonstrate for six clinically relevant statins that only UGT1A1, 1A3, and 2B7 contribute significantly to their lactonization. UGT1A3 appeared to have the highest lactonization capacity with marked differences in statin conversion rates: pitavastatin ≫ atorvastatin > cerivastatin > lovastatin > rosuvastatin (simvastatin not converted). Using in silico modeling we could identify a probable statin interaction region in the UGT binding pocket. Polymorphisms in these regions of UGT1A1, 1A3, and 2B7 may be a contributing factor in statin-induced myopathies, which could be used in personalization of statin therapy with improved safety.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.|Center for Systems Biology and Bioenergetics of the Nijmegen Center for Mitochondrial Disorders , 6500 HB Nijmegen, The Netherlands.
authors.forename: Tom J J
authors.initials: TJ
authors.lastname: Schirris
authors.affiliation: Computational Discovery and Design Group, Center for Molecular and Biomolecular Informatics (CMBI), Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.
authors.forename: Tina
authors.initials: T
authors.lastname: Ritschel
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Bilos
authors.affiliation: Center for Systems Biology and Bioenergetics of the Nijmegen Center for Mitochondrial Disorders , 6500 HB Nijmegen, The Netherlands.|Department of Pediatrics, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center , 6500 HB Nijmegen, The Netherlands.|Center for Systems Biology and Bioenergetics of the Nijmegen Center for Mitochondrial Disorders , 6500 HB Nijmegen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D002853:Chromatography, Liquid; D014453:Glucuronosyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D007783:Lactones / Q000737:chemistry*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D053719:Tandem Mass Spectrometry
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D014453:Glucuronosyltransferase
keywords: HMG-CoA reductase inhibitors; UGT homology models; acyl-coenzyme A; glucuronidation; lactonization; statin-induced myopathy; statins; uridine 5′-diphospho-glucuronosyltransferase (UGT)