Carbonyl reduction of warfarin: Identification and characterization of human warfarin reductases
| Autor: | Simona Sokolová, Vladimír Wsól, Lucie Havlíková, Petra Malátková |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
3-Hydroxysteroid Dehydrogenases CBR1 medicine.drug_class Metabolite Gene Expression Pharmacology 030226 pharmacology & pharmacy Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Aldehyde Reductase Escherichia coli medicine Humans heterocyclic compounds cardiovascular diseases Biotransformation Chromatography High Pressure Liquid Chemistry Carbonyl reduction Anticoagulant Aldo-Keto Reductase Family 1 Member C3 Warfarin Anticoagulants Stereoisomerism Metabolism Recombinant Proteins Culture Media Isoenzymes Alcohol Oxidoreductases Kinetics 030104 developmental biology Liver Hydroxyprostaglandin Dehydrogenases Microsomes Liver Microsome Oxidation-Reduction Drug metabolism medicine.drug |
| Zdroj: | Biochemical Pharmacology. 109:83-90 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2016.03.025 |
| Popis: | Warfarin is a widely used anticoagulant and, unfortunately, is a drug that is commonly implicated in serious adverse events including fatalities. Although several factors, including the metabolism of warfarin via CYP450, have been reported to affect the safety and efficacy of warfarin therapy, the wide variance in the warfarin dosage in patients has not been completely clarified. In addition to the oxidative metabolism of warfarin mediated by CYP450, reductive metabolism is involved in warfarin biotransformation. However, the reductive metabolism of warfarin has been largely unexplored and deserves further investigation. We studied warfarin reduction by human liver fractions and found a 9-fold higher velocity of warfarin reduction in the cytosol than in microsomes (Vmax=77.2 vs. 8.7pmol/mgprotein/min, respectively). Furthermore, of nine recombinant cytosolic carbonyl reducing enzymes tested for their ability to reduce warfarin, AKR1C3 and CBR1 were identified as warfarin reductases and their kinetic parameters were determined. The internal clearance of warfarin was 3 orders of magnitude higher with AKR1C3 than with CBR1 (CLint=65.922 vs. 0.070μl/mgprotein/min, respectively). This is the first time that warfarin reducing enzymes in human liver subcellular fraction have been identified. Moreover, we have described the chiral aspects of warfarin reduction using an HPLC method that enabled the detection of individual warfarin alcohol stereoisomers. Cytosol and AKR1C3 exhibit the stereoselective metabolism of (R)-warfarin to preferentially form (SR)-warfarin alcohol as the primary in vivo metabolite of warfarin. On the other hand, microsomes and CBR1 preferentially reduce (S)-warfarin to form (RS)-warfarin alcohol and (SS)-warfarin alcohol, respectively. |
| Databáze: | OpenAIRE |
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