Naturally Occurring Variants of Human Aldo-Keto Reductases with Reduced In Vitro Metabolism of Daunorubicin and Doxorubicin
| Autor: | K. Wayne Riggs, Thomas A. Grigliatti, Onkar S. Bains, Ronald E. Reid |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular 3-Hydroxysteroid Dehydrogenases CBR1 Carbonyl Reductase Daunorubicin Metabolite Aldo-Keto Reductases Biology Glyceraldehyde Polymorphism Single Nucleotide Mitochondrial Proteins chemistry.chemical_compound Gene Frequency Pharmacokinetics Aldehyde Reductase NAD(P)H Dehydrogenase (Quinone) medicine Humans 20-Hydroxysteroid Dehydrogenases Pharmacology chemistry.chemical_classification Aldo-keto reductase Aldo-Keto Reductase Family 1 Member C3 Hydroxysteroid Dehydrogenases Vitamin K 3 Metabolism Phenanthrenes Molecular biology Recombinant Proteins Alcohol Oxidoreductases Kinetics Enzyme Biochemistry chemistry Doxorubicin Indans Biocatalysis Hydroxyprostaglandin Dehydrogenases Molecular Medicine Oxidoreductases medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 335:533-545 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.110.173179 |
| Popis: | Doxorubicin (DOX) and daunorubicin (DAUN) are effective anticancer drugs; however, considerable interpatient variability exists in their pharmacokinetics. This may be caused by altered metabolism by nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in genes encoding aldo-keto reductases (AKRs) and carbonyl reductases. This study examined the effect of 27 ns-SNPs, in eight human genes, on the in vitro metabolism of both drugs to their major metabolites, doxorubicinol and daunorubicinol. Kinetic assays measured metabolite levels by high-performance liquid chromatography separation with fluorescence detection using purified, histidine-tagged, human wild-type, and variant enzymes. Maximal rate of activity (V(max)), substrate affinity (K(m)), turnover rate (k(cat)), and catalytic efficiency (k(cat)/K(m)) were determined. With DAUN as substrate, variants for three genes exhibited significant differences in these parameters compared with their wild-type counterparts: the A106T, R170C, and P180S variants significantly reduced metabolism compared with the AKR1C3 wild-type (V(max), 23-47% decrease; k(cat), 22-47%; k(cat)/K(m), 38-44%); the L311V variant of AKR1C4 significantly decreased V(max) (47% lower) and k(cat) and k(cat)/K(m) (both 43% lower); and the A142T variant of AKR7A2 significantly affected all kinetic parameters (V(max) and k(cat), 61% decrease; K(m), 156% increase; k(cat)/K(m), 85% decrease). With DOX, the R170C and P180S variants of AKR1C3 showed significantly reduced V(max) (41-44% decrease), k(cat) (39-45%), and k(cat)/K(m) (52-69%), whereas the A142T variant significantly altered all kinetic parameters for AKR7A2 (V(max), 41% decrease; k(cat), 44% decrease; K(m), 47% increase; k(cat)/K(m), 60% decrease). These findings suggest that ns-SNPs in human AKR1C3, AKR1C4, and AKR7A2 significantly decrease the in vitro metabolism of DOX and DAUN. |
| Databáze: | OpenAIRE |
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