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Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome

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Abstract

Purpose

The intracardiac synthesis of anthracycline alcohol metabolites (e.g., daunorubicinol) contributes to the pathogenesis of anthracycline-related cardiotoxicity. Cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- and without- DS.

Methods

Cardiac expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays using daunorubicin. The CBR1 polymorphism rs9024 was investigated by allelic discrimination with fluorescent probes. The contribution of CBRs/AKRs proteins to daunorubicin reductase activity was examined by multiple linear regression.

Results

CBR1 was the most abundant transcript (average relative expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most abundant protein (average relative expression; DS: 38%, non-DS: 35%). Positive associations between cardiac CBR1 protein levels and daunorubicin reductase activity were found for samples from donors with- and without- DS. Regression analysis suggests that sex, CBR1, AKR1A1, and AKR7A2 protein levels were significant contributors to cardiac daunorubicin reductase activity. CBR1 rs9024 genotype status impacts on cardiac CBR1 expression in non-DS hearts.

Conclusions

CBR1, AKR1A1, and AKR7A2 protein levels point to be important determinants for predicting the synthesis of cardiotoxic daunorubicinol in heart.

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Abbreviations

aCGH:

Array comparative genomic hybridization

ACTB:

Actin B

AKR1A1:

Aldo-keto reductase family 1, member A1

AKR1C3:

Aldo-keto reductase family 1, member C3

AKR7A2:

Aldo-keto reductase family 7, member A2

AKRs:

Aldo-keto reductases

CBR1:

Carbonyl reductase 1

CBR3:

Carbonyl reductase 3

CBRs:

Carbonyl reductases

DS:

Down syndrome

LOD:

Limit of detection

LOQ:

Limit of quantification

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Acknowledgments and Disclosures

Adolfo Quiñones-Lombraña and Daniel Ferguson contributed equally to this manuscript. This work was supported by the National Institute of General Medical Sciences [GM073646].

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, New York, USA

    Adolfo Quiñones-Lombraña, Daniel Ferguson, James L. Kalabus, Almedina Redzematovic & Javier G. Blanco

  2. Department of Biostatistics School of Public Health and Health Professions, The State University of New York at Buffalo, Buffalo, New York, USA

    Rachael Hageman Blair

  3. Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, 470 Kapoor Hall, Buffalo, New York, 14214-8033, USA

    Javier G. Blanco

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  1. Adolfo Quiñones-Lombraña
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  2. Daniel Ferguson
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Correspondence to Javier G. Blanco.

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Quiñones-Lombraña, A., Ferguson, D., Hageman Blair, R. et al. Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome. Pharm Res 31, 1644–1655 (2014). https://doi.org/10.1007/s11095-013-1267-1

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  • DOI: https://doi.org/10.1007/s11095-013-1267-1

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