Abstract
Secondary alcohol metabolites and reactive oxygen species mediate cardiomyopathy induced by cumulative doses of antitumor anthracyclines, such as doxorubicin and epirubicin. Epirubicin exhibits a defective conversion to both toxic species, thereby inducing cardiotoxicity at doses higher than equiactive to doxorubicin; however, the gain in cardiac tolerability seems to be marginal compared with the magnitude of the metabolic defects of epirubicin. Cardiomyopathy may occur independent of toxic metabolites if a given anthracycline tends to accumulate in the heart; therefore, we characterized whether epirubicin showed an unusual accumulation in human myocardial strips incubated in plasma. Epirubicin exhibited a higher uptake and reached myocardial levels 2 times higher than those of doxorubicin. Epirubicin also showed a unique metabolization to doxorubicinolone, the product of epirubicin deglycosidation and carbonyl reduction. In diffusing from the strips to plasma, doxorubicinolone caused membrane permeation effects that augmented epirubicin elimination. Experiments with purified doxorubicinolone showed that the efflux of 1 mol doxorubicinolone promoted the concomitant elimination of as many as ∼40 mol epirubicin. Doxorubicinolone could also diffuse from plasma back to the strips, causing a permeation effect that promoted epirubicin reuptake; however, this reverse process was slower and less potent. On balance, doxorubicinolone efflux diminished the epirubicin to doxorubicin accumulation ratio to ∼1.5. These results suggest that the cardiac tolerability of epirubicin is limited by its accumulation in the heart and that such accumulation would be even higher in the absence of doxorubicinolone formation and efflux. These results may also serve guidelines for developing noncardiotoxic anthracyclines.
Footnotes
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↵1 In these experiments, quercetin was used high enough (100 μM) to inhibit epirubicinol formation by 60 to 70%. Therefore, the effects of doxorubicinolone[in → out] on epirubicinol levels must be intended as net changes versus strips, which also formed fewer epirubicinol in response to excess quercetin. The same concept applies to experiments with doxorubicinolone[out → in].
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↵2 Epirubicin did not differ from doxorubicin in regard to the pKa of the protonatable NH2 residue in the sugar. Protonation-sequestration of epirubicin was only favored by its higher lipophilicity and diffusion in the acidic organelles (Salvatorelli et al., 2006).
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↵3 7-Deoxydoxorubicinolone originates from disproportionation of two semiquinone free radicals, with regeneration of 1 mol doxorubicin and concomitant carbonyl reduction and reductive deglycosidation of another 1 mol doxorubicin (Salvatorelli et al., 2006). In the present study, 7-deoxydoxorubicinolone averaged 0.022 ± 0.005 μM and could only be recovered from the membrane fraction.
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This work was supported by the Associazione Italiana Ricerca sul Cancro and University Campus Bio-Medico of Rome [Intramural Project “Cardio-Oncology”].
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E.S. and P.M. contributed equally to this work.
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doi:10.1124/jpet.108.149260.
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ABBREVIATIONS: CHF, congestive heart failure; Cmax, peak plasma concentration; ROS, reactive oxygen species; AL1576, 2,7-difluorospirofluorene-9,5′-imidazolidine-2′,4′-dione; quercetin, 3,3′,4′,5,7-pentahydroxyflavone.
- Received December 2, 2008.
- Accepted January 13, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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