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Drug Metabolism and Disposition Fast Forward
First published on March 5, 2008; DOI: 10.1124/dmd.108.020388

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Ryan H Takahashi
Onkar S Bains
Ronald E Reid
K. Wayne Riggs
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Received for publication January 7, 2008.
Revised February 20, 2008.
Accepted for publication February 27, 2008.

Aldo-keto reductase 1C2 fails to metabolize doxorubicin and daunorubicin in vitro

Ryan H Takahashi 1, Onkar S Bains 1, Tom A Pfiefer 2, Thomas A Grigliatti 3, Ronald E Reid 3, K. Wayne Riggs 4*

1 University of British Columbia 2 Centre for Drug Research and Development 3 Unversity of British Columbia 4 The University of British Columbia

* Address correspondence to: E-mail: riggskw{at}interchange.ubc.ca

Abstract

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. While the mechanism for this side effect has not yet been identified, the alcohol metabolites formed during DAUN and DOX therapies have been implicated. The alcohol metabolites of DAUN and DOX, DAUNol and 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, AKR1A1 and AKR1C2, with DAUN and DOX as substrates. Using purified histidine-tagged recombinant proteins and the direct measurement of metabolite formation with an HPLC-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 pmol/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.


Key words: anticancer agents, enzyme kinetics, human CYP enzymes, recombinant proteins, reductases


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