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Protective Effect of 23-hydroxybetulinic Acid on Doxorubicin-Induced Cardiotoxicity: A Correlation With the Inhibition of Carbonyl Reductase-Mediated Metabolism

Protective Effect of 23-hydroxybetulinic Acid on Doxorubicin-Induced Cardiotoxicity: A Correlation With the Inhibition of Carbonyl Reductase-Mediated Metabolism

Fang Zhou, Gang Hao, Jingwei Zhang, Yuanting Zheng, Xiaolan Wu, Kun Hao, Fang Niu, Dan Luo, Yuan Sun, Liang Wu, Wencai Ye, Guangji Wang

Br J Pharmacol. 2015 Dec;172(23):5690-703.

PMID: 25363561

Abstract:

Background and purpose:
The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. 23-Hydroxybetulinic acid (23-HBA), isolated from Pulsatilla chinensis, enhances the anticancer effect of doxorubicin while simultaneously reducing its cardiac toxicity, but does not affect the concentration of doxorubicin in the plasma and heart. As the metabolite doxorubicinol is more potent than doxorubicin at inducing cardiac toxicity, in the present study we aimed to clarify the role of doxorubicinol in the protective effect of 23-HBA.
Experimental approach:
Doxorubicin was administered to mice for two weeks in the presence or absence of 23-HBA. The heart pathology, function, myocardial enzymes and accumulation of doxorubicin and doxorubicinol were then analysed. A cellular pharmacokinetic study of doxorubicin and doxorubicinol, carbonyl reductase 1 (CBR1) interference and molecular docking was performed in vitro.
Key results:
23-HBA alleviated the doxorubicin-induced cardiotoxicity in mice, and this was accompanied by inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts. In H9c2 cells, the protective effect of 23-HBA was shown to be closely associated with a decreased rate and extent of accumulation of doxorubicinol in mitochondria and nuclei. siRNA and docking analysis demonstrated that CBR1 has a crucial role in doxorubicin-mediated cardiotoxicity and 23-HBA inhibits this metabolic pathway.
Conclusions and implications:
Inhibition of CBR-mediated doxorubicin metabolism might be one of the protective mechanisms of 23-HBA against doxorubicin-induced cardiotoxicity. The present study provides a new research strategy guided by pharmacokinetic theory to elucidate the mechanism of drugs with unknown targets.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP85999402-B	23-Hydroxybetulinic acid		85999-40-2	Price

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