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Inhibition of Polymorphic Human Carbonyl Reductase 1 (CBR1) by the Cardioprotectant Flavonoid 7-monohydroxyethyl Rutoside (monoHER)

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Abstract

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 IC50 values of monoHER were lower for CBR1 I88 compared to CBR1 V88 for the substrates daunorubicin and doxorubicin (daunorubicin, IC50-CBR1 I88 = 164 μM vs. IC50-CBR1 V88 = 219 μM; doxorubicin, IC50-CBR1 I88 = 37 μM vs. IC50-CBR1 V88 = 59 μM; p < 0.001). Similarly, the flavonoids triHER and quercetin exhibited lower IC50 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 μM. MonoHER acted as an uncompetitive CBR1 inhibitor for the small quinone substrate menadione Ki = 33 ± 17 μM.

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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Abbreviations

NADPH:

nicotinamide adenine dinucleotide 2′-phosphate

triHER:

5,7,2 trihydroxiethylrutoside (Venoruton®)

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Acknowledgments

National Institutes of Health/National Institute of General Medical Sciences Grant RO1GM73646 to J.G.B supported this work.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 545 Cooke Hall, Buffalo, New York, 14260-1200, USA

    Vanessa Gonzalez-Covarrubias, James L. Kalabus & Javier G. Blanco

Authors
  1. Vanessa Gonzalez-Covarrubias
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  2. James L. Kalabus
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  3. Javier G. Blanco
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Correspondence to Javier G. Blanco.

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Gonzalez-Covarrubias, V., Kalabus, J.L. & Blanco, J.G. Inhibition of Polymorphic Human Carbonyl Reductase 1 (CBR1) by the Cardioprotectant Flavonoid 7-monohydroxyethyl Rutoside (monoHER). Pharm Res 25, 1730–1734 (2008). https://doi.org/10.1007/s11095-008-9592-5

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  • DOI: https://doi.org/10.1007/s11095-008-9592-5

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