| Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER). | |
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MedLine Citation:
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PMID: 18449627 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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PURPOSE: Carbonyl reductase 1 (CBR1) reduces the anticancer anthracyclines doxorubicin and daunorubicin into the cardiotoxic metabolites doxorubicinol and daunorubicinol. We evaluated whether the cardioprotectant monoHER inhibits the activity of polymorphic CBR1. METHODS: We performed enzyme kinetic studies with monoHER, CBR1 (CBR1 V88 and CBR1 I88) and anthracycline substrates. We also characterized CBR1 inhibition by the related flavonoids triHER and quercetin. RESULTS: MonoHER inhibited the activity of CBR1 V88 and CBR1 I88 in a concentration-dependent manner. The IC(50) values of monoHER were lower for CBR1 I88 compared to CBR1 V88 for the substrates daunorubicin and doxorubicin (daunorubicin, IC(50)-CBR1 I88 = 164 microM vs. IC(50)-CBR1 V88 = 219 microM; doxorubicin, IC(50)-CBR1 I88 = 37 microM vs. IC(50)-CBR1 V88 = 59 microM; p < 0.001). Similarly, the flavonoids triHER and quercetin exhibited lower IC(50) values for CBR1 I88 compared to CBR1 V88 (p < 0.001). MonoHER acted as a competitive CBR1 inhibitor when using daunorubicin as a substrate Ki = 45 +/- 18 microM. MonoHER acted as an uncompetitive CBR1 inhibitor for the small quinone substrate menadione Ki = 33 +/- 17 microM. CONCLUSIONS: The cardioprotectant monoHER inhibits CBR1 activity. CBR1 V88I genotype status and the type of anthracycline substrate dictate the inhibition of CBR1 activity. |
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Authors:
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Vanessa Gonzalez-Covarrubias; James L Kalabus; Javier G Blanco |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-05-01 |
Journal Detail:
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Title: Pharmaceutical research Volume: 25 ISSN: 0724-8741 ISO Abbreviation: Pharm. Res. Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-06-04 Completed Date: 2008-08-29 Revised Date: 2012-05-04 |
Medline Journal Info:
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Nlm Unique ID: 8406521 Medline TA: Pharm Res Country: United States |
Other Details:
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Languages: eng Pagination: 1730-4 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 545 Cooke Hall, Buffalo, New York 14260-1200, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Alcohol Oxidoreductases
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antagonists & inhibitors*,
genetics Antibiotics, Antineoplastic / pharmacology Cardiotonic Agents / pharmacology* Data Interpretation, Statistical Daunorubicin / pharmacology Doxorubicin / pharmacology Enzyme Inhibitors / pharmacology* Genotype Humans Hydroxyethylrutoside / analogs & derivatives*, pharmacology Kinetics Recombinant Proteins / chemistry |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM073646/GM/NIGMS NIH HHS; R01 GM073646-04/GM/NIGMS NIH HHS; R01GM73646/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/7-monohydroxyethylrutoside; 0/Antibiotics, Antineoplastic; 0/Cardiotonic Agents; 0/Enzyme Inhibitors; 0/Hydroxyethylrutoside; 0/Recombinant Proteins; 20830-81-3/Daunorubicin; 23214-92-8/Doxorubicin; EC 1.1.-/Alcohol Oxidoreductases |
| Comments/Corrections | |
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