Aldo-Keto Reductase 1C2 Fails to Metabolize Doxorubicin and Daunorubicin in Vitro
The anthracycline drugs are important for the treatment of a number of malignancies; however, their clinical use is associated with dose-dependent severe chronic cardiotoxicity. Although the mechanism for this side effect has not yet been identified, the alcohol metabolites formed during daunorubici...
Saved in:
Published in | Drug metabolism and disposition Vol. 36; no. 6; pp. 991 - 994 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.06.2008
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The anthracycline drugs are important for the treatment of a number of malignancies; however, their clinical use is associated
with dose-dependent severe chronic cardiotoxicity. Although the mechanism for this side effect has not yet been identified,
the alcohol metabolites formed during daunorubicin (DAUN) and doxorubicin (DOX) therapies have been implicated. The alcohol
metabolites of DAUN and DOX, daunorubicinol (DAUNol) and doxorubicinol (DOXol), respectively, are generated through reduction
of the C-13 carbonyl function, which is reportedly mediated by members of the aldo-keto reductase and carbonyl reductase families
of proteins. In our search for potential biomarkers for the occurrence of this side effect, we examined the activity of recombinant
aldo-keto reductase enzymes, aldo-keto reductase (AKR) 1A1 and AKR1C2, with DAUN and DOX as substrates. Using purified histidine-tagged
recombinant proteins and the direct measurement of metabolite formation with a high-performance liquid chromatography-fluorescence
assay, we did not observe DAUNol or DOXol generation in vitro by AKR1C2, whereas AKR1A1 did catalyze the reduction reactions.
DAUNol was generated by AKR1A1 at a rate of 1.71 ± 0.09 nmol/min/mg protein, and a low level of DOXol was produced by AKR1A1;
however, it was below the limits of quantification for the method. These data suggest that the generation of DAUNol or DOXol
by AKR1C2 metabolism in vivo is unlikely to occur during anthracycline treatment. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.108.020388 |