Lipid peroxidation has been proposed to mediate
cardiotoxicity induced by
doxorubicin (DOX) and other anticancer
anthracyclines; however, there have been reports showing that DOX can also inhibit lipid peroxidation. Here we characterized the effects of DOX on the oxo-ferryl moiety [Fe(IV)=O, Mb(IV)] of H(2)O(2)-activated
myoglobin, a
lipid oxidant likely formed in the heart during treatment with DOX. Mb(IV) was formed in vitro by reacting 100 microM H(2)O(2) with 50 microM horse heart
metmyoglobin (Mb(III)). Spectral studies showed that DOX reduced Mb(IV) to Mb(III), half-maximal regeneration of Mb(III) occurring at approximately 18 microM DOX. Comparisons between DOX, its aglycone
doxorubicinone, and other approved or investigational
anthracyclines or model compounds (
daunorubicin,
idarubicin,
aclarubicin, and
naphthazarin), showed that DOX reduced Mb(IV) through the
hydroquinone moiety of its tetracyclic ring. DOX inhibited Mb(IV)-dependent peroxidation of
arachidonic acid, suppressing the formation of
thiobarbituric acid-reactive substances with an IC(50) of approximately 18 microM. Lipid peroxidation was inhibited also by the
hydroquinone-containing
daunorubicin and
idarubicin but not by the
hydroquinone-deficient
aclarubicin; moreover, neither simple
hydroquinone nor other known Mb(IV)
reductants (ascorbate,
glutathione, and
ergothioneine) reached measurable IC(50)s in a micromolar range. DOX-dependent inhibition of lipid peroxidation correlated with its ability to reduce Mb(IV) to Mb(III) in competition with
arachidonic acid (r = 0.83, P = 0.029); it did not correlate with its ability to scavenge other
free radical species [like e.g., peroxyl radicals generated through the thermal decomposition of 2,2'-azo-bis(2-amidinopropane)]. DOX reduced Mb(IV) and inhibited lipid peroxidation also when H(2)O(2), Mb(III) and
arachidonic acid were reacted in cytosol of human myocardial biopsies, a model developed to predict the cardiotoxic mode of action of DOX in patients. These results illustrate "
antioxidant" properties of DOX, mediated by reduction of Mb(IV) to Mb(III), and cast doubts on lipid peroxidation as a causative mechanism of
anthracycline-induced
cardiotoxicity.