| Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin. | |
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MedLine Citation:
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PMID: 18276838 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aldo-keto reductases (AKRs) are a class of NADPH-dependent oxidoreductases that have been linked to metabolism of the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN). Although widely used, cardiotoxicity continues to be a serious side effect that may be linked to metabolites or reactive intermediates generated in their metabolism. In this study we examine the little known effects of nonsynonymous single nucleotide polymorphisms of human AKR1A1 on the metabolism of these drugs to their alcohol metabolites. Expressed and purified from bacteria using affinity chromatography, the AKR1A1 protein with a single histidine (6x-His) tag exhibited the greatest activity using two test substrates: p-nitrobenzaldehyde (5.09 +/- 0.16 micromol/min/mg of purified protein) and DL-glyceraldehyde (1.24 +/- 0.17 micromol/min/mg). These activities are in agreement with published literature values of nontagged human AKR1A1. The 6x-His-tagged AKR1A1 wild type and allelic variants, E55D and N52S, were subsequently examined for metabolic activity using DAUN and DOX. The tagged variants showed significantly reduced activities (1.10 +/- 0.42 and 0.72 +/- 0.47 nmol of daunorubicinol (DAUNol) formed/min/mg of purified protein for E55D and N52S, respectively) compared with the wild type (2.34 +/- 0.71 nmol/min/mg). The wild type and E55D variant metabolized DOX to doxorubicinol (DOXol); however, the levels fell below the limit of quantitation (25 nM). The N52S variant yielded no detectable DOXol. A kinetic analysis of the DAUN reductase activities revealed that both amino acid substitutions lead to reduced substrate affinity, measured as significant increases in the measured K(m) for the reduction reaction by AKR1A1. Hence, it is possible that these allelic variants can act as genetic biomarkers for the clinical development of DAUN-induced cardiotoxicity. |
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Authors:
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Onkar S Bains; Ryan H Takahashi; Tom A Pfeifer; Thomas A Grigliatti; Ronald E Reid; K Wayne Riggs |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-02-14 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 36 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2008 May |
Date Detail:
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Created Date: 2008-04-21 Completed Date: 2008-08-18 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 904-10 Citation Subset: IM |
Affiliation:
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Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, 2146 East Mall, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldehyde Reductase
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genetics,
metabolism* Alleles Antibiotics, Antineoplastic / metabolism* Biological Markers / metabolism Daunorubicin / metabolism* Doxorubicin / metabolism Genetic Variation Humans Recombinant Proteins / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Biological Markers; 0/Recombinant Proteins; 20830-81-3/Daunorubicin; 23214-92-8/Doxorubicin; EC 1.1.1.21/Aldehyde Reductase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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