Anthracycline-related
cardiotoxicity correlates with cardiac
anthracycline accumulation and bioactivation to secondary alcohol metabolites or
reactive oxygen species (ROS), such as
superoxide anion (O₂·⁻) and
hydrogen peroxide H₂O₂). We reported that in an ex vivo human myocardial strip model, 3 or 10 μM
amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] accumulated to a lower level compared with equimolar
doxorubicin or
epirubicin (J Pharmacol Exp Ther 341:464-473, 2012). We have characterized how
amrubicin converted to ROS or secondary alcohol metabolite in comparison with
doxorubicin (that formed both toxic species) or
epirubicin (that lacked ROS formation and showed an impaired conversion to alcohol metabolite).
Amrubicin and
doxorubicin partitioned to mitochondria and caused similar elevations of H₂O₂, but the mechanisms of H₂O₂ formation were different.
Amrubicin produced H₂O₂ by enzymatic reduction-oxidation of its
quinone moiety, whereas
doxorubicin acted by inducing mitochondrial uncoupling. Moreover, mitochondrial
aconitase assays showed that 3 μM
amrubicin caused an O₂·⁻-dependent reversible inactivation, whereas
doxorubicin always caused an irreversible inactivation. Low concentrations of
amrubicin therefore proved similar to
epirubicin in sparing mitochondrial
aconitase from irreversible inactivation. The soluble fraction of human myocardial strips converted
doxorubicin and
epirubicin to secondary alcohol metabolites that irreversibly inactivated cytoplasmic
aconitase; in contrast, strips exposed to
amrubicin failed to generate its secondary alcohol metabolite,
amrubicinol, and only occasionally exhibited an irreversible inactivation of cytoplasmic
aconitase. This was caused by competing pathways that favored formation and complete or near-to-complete elimination of 9-deaminoamrubicinol. These results characterize
amrubicin metabolic advantages over
doxorubicin and
epirubicin, which may correlate with
amrubicin cardiac safety in preclinical or clinical settings.