Daunorubicin and its hydroxy metabolite in cardiomyocytes: insights into cellular kinetics, toxicity, DNA damage, and dexrazoxane-induced cardioprotection

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F25%3A10499660" target="_blank" >RIV/00216208:11150/25:10499660 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/25:10499660

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=haRZX9yjZ2" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=haRZX9yjZ2</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00204-025-04095-z" target="_blank" >10.1007/s00204-025-04095-z</a>

Result language

angličtina

Original language name

Daunorubicin and its hydroxy metabolite in cardiomyocytes: insights into cellular kinetics, toxicity, DNA damage, and dexrazoxane-induced cardioprotection

Original language description

Anthracycline anticancer agents, such as daunorubicin and doxorubicin, rank among the most effective and widely used anticancer drugs. However, their benefit is markedly reduced by the risk of severe cardiotoxicity. Anthracyclines undergo metabolic reduction of the side chain carbonyl group, producing hydroxy metabolites implicated in the cardiotoxicity. This study investigated toxicity, metabolism and cellular disposition of daunorubicin and its hydroxy metabolite, daunorubicinol, in isolated rat neonatal cardiomyocytes. Daunorubicin induced concentration-dependent cytotoxicity, whereas the toxicity of exogenously administered daunorubicinol was significantly lower despite induction of similar DNA damage. UHPLC-MS analyses revealed that daunorubicin rapidly penetrates cardiomyocytes and is metabolized to daunorubicinol, which is then released from the cells. The intracellular concentration of daunorubicinol was consistently lower than that of daunorubicin, indicating a reduced tendency for daunorubicinol to accumulate in cardiomyocytes. P-glycoprotein 1 has been shown to actively facilitate the efflux of both daunorubicin and daunorubicinol from cardiomyocytes. Dexrazoxane, the only approved agent for anthracycline cardiotoxicity prevention, did not affect the cellular metabolism or disposition of daunorubicin or its hydroxy metabolite, but it effectively reduced not only daunorubicin-induced cardiotoxicity, but also provided protection against the lower toxicity of daunorubicinol. Moreover, dexrazoxane reduced DNA damage induced by both daunorubicin and its hydroxy metabolite. These findings suggest that daunorubicin is the primary driver of cardiomyocyte cytotoxicity, while its hydroxy metabolite, daunorubicinol, plays a more limited role, challenging the notion that it serves as a significant toxic reservoir.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Archives of Toxicology

ISSN

0340-5761

e-ISSN

1432-0738

Volume of the periodical

99

Issue of the periodical within the volume

9

Country of publishing house

DE - GERMANY

Number of pages

18

Pages from-to

3751-3768

UT code for WoS article

001503461700001

EID of the result in the Scopus database

2-s2.0-105007685032