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Chalcone inhibition of anthracycline secondary alcohol metabolite formation in rabbit and human heart cytosol.

Abstract：

:Antineoplastic therapy with anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) is limited by the possible development of a dose-related cardiomyopathy. Secondary alcohol metabolites like doxorubicinol (DOXol) and daunorubicinol (DNRol), formed by cytoplasmic two-electron reductases, have been implicated as potential mediators of anthracycline-induced cardiomyopathy. In the present study, we characterized the effects of 12 chalcones on the formation of anthracycline secondary alcohol metabolites by rabbit or human heart cytosol and compared them with those of quercetin and other flavonoids. Both chalcones and flavonoids inhibited DOXol or DNRol formation in isolated rabbit heart cytosol. Structure--activity relationships showed that inhibition by chalcones was determined primarily by the position of hydroxyl groups in their phenolic A and B rings. In particular, the presence of a hydroxyl group at C-4' in the A ring was an important determinant of the inhibitory activity of chalcones. Among chalcones, 2',4',2-trihydroxychalcone exhibited the highest inhibition of both DOXol and DRNol formation, but it proved less efficient than quercetin. Different results were obtained with isolated human heart cytosol: in the latter, 2',4',2-trihydroxychalcone and other hydroxychalcones inhibited both DOXol and DNRol formation, whereas quercetin and other flavonoids inhibited DNRol formation but failed to inhibit or slightly stimulated DOXol formation. These results identify chalcones as versatile inhibitors of the cytoplasmic reductases that convert anthracyclines to cardiotoxic secondary alcohol metabolites.

journal_name

Chem Res Toxicol

journal_title

Chemical research in toxicology

authors

Silvestrini A,Meucci E,Vitali A,Giardina B,Mordente A

doi

10.1021/tx060159a

subject

Has Abstract

pub_date

2006-11-01 00:00:00

pages

1518-24

issue

11

eissn

0893-228X

issn

1520-5010

journal_volume

19

pub_type

杂志文章

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