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Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

The present study aimed to investigate the role of expression of daunorubicin-metabolizing enzymes carbonyl reductase 1 and 3 (CBR1 and CBR3) on the in vitro cytotoxicity of daunorubicin in primary acute myeloid leukemia (AML) cells and the effect of genetic variants in CBR1 and CBR3 on the plasma pharmacokinetics of daunorubicin and daunorubicinol (DOL) in AML patients.

Methods

RNA expression of CBR1 and CBR3, intracellular daunorubicin and DOL levels, and in vitro cytotoxicity of daunorubicin were measured in bone marrow mononuclear cells of 104 adult AML patients. Plasma pharmacokinetics of daunorubicin and DOL was measured in 24 patients receiving daunorubicin-based induction chemotherapy for AML.

Results

Increased expression of CBR1 significantly reduced the in vitro cytotoxicity of daunorubicin and also positively correlated with intracellular DOL levels. Polymorphisms in CBR1 and CBR3 did not show any association with intracellular daunorubicin or DOL levels, but there was a trend towards significant increase in plasma daunorubicin systemic exposure in patients with a variant genotype for CBR1 polymorphism rs25678.

Conclusions

This pilot study suggests that CBR1 RNA expression may be helpful in identifying AML patients at risk of developing resistance or toxicity to daunorubicin due to increased formation of DOL. Further confirmation of these findings in a larger sample pool would be required to determine the applicability of these results. Inhibition of CBR1 can be an option to improve the efficacy and prevent toxicity related to the treatment. Influence of daunorubicin and DOL plasma levels on clinical outcome, if any, remains to be evaluated.

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Acknowledgments

We gratefully acknowledge the help provided by Dr. Carl J Panetta, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN in checking our noncompartmental PK analysis and providing his valuable input in revising this manuscript. We also acknowledge Dr. Eunice S. Edison and Ms. M. Ezhilpavai for critically reviewing the revised manuscript. This study was supported by the Department of Biotechnology, India, grant no: BT/01/COE/08/03. Ajay Abraham is supported by a grant from the University Grants Commission, India.

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Authors and Affiliations

  1. Department of Haematology, Christian Medical College, Vellore, 632004, India

    Savitha Varatharajan, Ajay Abraham, R. V. Shaji, Rayaz Ahmed, Aby Abraham, Biju George, Alok Srivastava, Mammen Chandy, Vikram Mathews & Poonkuzhali Balasubramanian

  2. Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, USA

    Wei Zhang

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  1. Savitha Varatharajan
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  2. Ajay Abraham
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Correspondence to Poonkuzhali Balasubramanian.

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Varatharajan, S., Abraham, A., Zhang, W. et al. Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia. Eur J Clin Pharmacol 68, 1577–1586 (2012). https://doi.org/10.1007/s00228-012-1291-9

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  • DOI: https://doi.org/10.1007/s00228-012-1291-9

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