Chalcone Inhibition of Anthracycline Secondary Alcohol Metabolite Formation in Rabbit and Human Heart Cytosol

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• 作者：Andrea Silvestrini ; Elisabetta Meucci ; Alberto Vitali ; Bruno Giardina ; Alvaro Mordente
• 刊名：Chemical Research in Toxicology
• 出版年：2006
• 出版时间：November 2006
• 年：2006
• 卷：19
• 期：11
• 页码：1518 - 1524
• 全文大小：152K
• 年卷期：v.19,no.11(November 2006)
• ISSN：1520-5010

文摘

Antineoplastic therapy with anthracyclines like doxorubicin (DOX) and daunorubicin (DNR) is limitedby the possible development of a dose-related cardiomyopathy. Secondary alcohol metabolites likedoxorubicinol (DOXol) and daunorubicinol (DNRol), formed by cytoplasmic two-electron reductases,have been implicated as potential mediators of anthracycline-induced cardiomyopathy. In the presentstudy, we characterized the effects of 12 chalcones on the formation of anthracycline secondary alcoholmetabolites by rabbit or human heart cytosol and compared them with those of quercetin and otherflavonoids. Both chalcones and flavonoids inhibited DOXol or DNRol formation in isolated rabbit heartcytosol. Structure-activity relationships showed that inhibition by chalcones was determined primarilyby the position of hydroxyl groups in their phenolic A and B rings. In particular, the presence of ahydroxyl 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 DRNolformation, but it proved less efficient than quercetin. Different results were obtained with isolated humanheart cytosol: in the latter, 2',4',2-trihydroxychalcone and other hydroxychalcones inhibited both DOXoland DNRol formation, whereas quercetin and other flavonoids inhibited DNRol formation but failed toinhibit or slightly stimulated DOXol formation. These results identify chalcones as versatile inhibitors ofthe cytoplasmic reductases that convert anthracyclines to cardiotoxic secondary alcohol metabolites.