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Anthracycline Metabolism and Toxicity in Human Myocardium: Comparisons between Doxorubicin, Epirubicin, and a Novel Disaccharide Analogue with a Reduced Level of Formation and [4Fe-4S] Reactivity of Its Secondary Alcohol Metabolite

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Department of Drug Sciences, G. D'Annunzio University School of Pharmacy, and Department of Cardiac Surgery, G. D'Annunzio University School of Medicine, Chieti; Institute of Pharmacology, Catholic University School of Medicine, Rome; and Menarini Ricerche S. p. A., Pomezia (Rome), Italy
Cite this: Chem. Res. Toxicol. 2000, 13, 12, 1336–1341
Publication Date (Web):November 30, 2000
https://doi.org/10.1021/tx000143z
Copyright © 2000 American Chemical Society

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    Abstract

    Secondary alcohol metabolites have been proposed to mediate chronic cardiotoxicity induced by doxorubicin (DOX) and other anticancer anthracyclines. In this study, NADPH-supplemented human cardiac cytosol was found to reduce the carbonyl group in the side chain of the tetracyclic ring of DOX, producing the secondary alcohol metabolite doxorubicinol (DOXol). A decrease in the level of alcohol metabolite formation was observed by replacing DOX with epirubicin (EPI), a less cardiotoxic analogue characterized by an axial-to-equatorial epimerization of the hydroxyl group at C-4 in the amino sugar bound to the tetracyclic ring (daunosamine). A similar decrease was observed by replacing DOX with MEN 10755, a novel anthracycline with preclinical evidence of reduced cardiotoxicity. MEN 10755 is characterized by the lack of a methoxy group at C-4 in the tetracyclic ring and by intercalation of 2,6-dideoxy-l-fucose between daunosamine and the aglycone. Multiple comparisons with methoxy- or 4-demethoxyaglycones, and a number of mono- or disaccharide 4-demethoxyanthracyclines, showed that both the lack of the methoxy group and the presence of a disaccharide moiety limited alcohol metabolite formation by MEN 10755. Studies with enzymatically generated or purified anthracycline secondary alcohols also showed that the presence of a disaccharide moiety, but not the lack of a methoxy group, made the metabolite of MEN 10755 less reactive with the [4Fe-4S] cluster of cytoplasmic aconitase, as evidenced by its limited reoxidation to the parent carbonyl anthracycline and by a reduced level of delocalization of Fe(II) from the cluster. Collectively, these studies (i) characterize the different influence of methoxy and sugar substituents on the formation and [4Fe-4S] reactivity of anthracycline secondary alcohols, (ii) lend support to the role of alcohol metabolites in anthracycline-induced cardiotoxicity, as they demonstrate that the less cardiotoxic EPI and MEN 10755 share a reduction in the level of formation of such metabolites, and (iii) suggest that the cardiotoxicity of MEN 10755 might be further decreased by the reduced [4Fe-4S] reactivity of its alcohol metabolite.

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    *

     To whom correspondence should be addressed:  Department of Drug Sciences, G. D'Annunzio University School of Pharmacy, Via dei Vestini, 66013 Chieti, Italy. Phone: 011-39-0871-3555237. Fax: 011-39-0871-3555315. E-mail: [email protected].

     Department of Drug Sciences, G. D'Annunzio University School of Pharmacy.

     Institute of Pharmacology, Catholic University School of Medicine.

    §

     Department of Cardiac Surgery, G. D'Annunzio University School of Medicine.

     Menarini Ricerche S. p. A., Pomezia (Rome).

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