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.