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Doxorubicin Metabolism and Toxicity in Human Myocardium:  Role of Cytoplasmic Deglycosidation and Carbonyl Reduction

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Institutes of Pharmacology and Biochemistry, Catholic University School of Medicine, Rome, Italy, and Department of Drug Sciences, G. D'Annunzio University School of Pharmacy, Chieti, Italy
Cite this: Chem. Res. Toxicol. 2000, 13, 5, 414–420
Publication Date (Web):April 14, 2000
Copyright © 2000 American Chemical Society

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    The anthracycline doxorubicin (DOX) is an exceptionally good antineoplastic agent, but its use is limited by formation of metabolites which induce acute and chronic cardiac toxicities. Whereas the acute toxicity is mild, the chronic toxicity can produce a life-threatening cardiomyopathy. Studies in laboratory animals are of limited value in predicting the structure and reactivity of toxic metabolites in humans; therefore, we used an ethically acceptable system which is suitable for exploring DOX metabolism in human myocardium. The system involves cytosolic fractions from myocardial samples obtained during aorto-coronary bypass grafting. After reconstitution with NADPH and DOX, these fractions generate the alcohol metabolite doxorubicinol (DOXol) as well as DOX deoxyaglycone and DOXol hydroxyaglycone, reflecting reduction of the side chain carbonyl group, reductase-type deglycosidation of the anthracycline, and hydrolase-type deglycosidation followed by carbonyl reduction, respectively. The efficiency of each metabolic route has been evaluated at low and high DOX:protein ratios, reproducing acute, single-dose and chronic, multiple-dose regimens, respectively. Low DOX:protein ratios increase the efficiency of formation of DOX deoxyaglycone and DOXol hydroxyaglycone but decrease that of DOXol. Conversely, high DOX:protein ratios facilitate the formation of DOXol but impair reductase- or hydrolase-type deglycosidation and uncouple hydrolysis from carbonyl reduction, making DOXol accumulate at levels higher than those of DOX deoxyaglycone and DOXol hydroxyaglycone. Structure−activity considerations have suggested that aglycones and DOXol may inflict cardiac damage by inducing oxidative stress or by perturbing iron homeostasis, respectively. Having characterized the influence of DOX:protein ratios on deglycosidation or carbonyl reduction, we propose that the benign acute toxicity should be attributed to the oxidant activity of aglycones, whereas the life-threatening chronic toxicity should be attributed to alterations of iron homeostasis by DOXol. This picture rationalizes the limited protective efficacy of antioxidants against chronic cardiomyopathy vis-à-vis the better protection offered by iron chelators, and forms the basis for developing analogues which produce less DOXol.

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     Institute of Pharmacology, Catholic University School of Medicine.

     Institute of Biochemistry, Catholic University School of Medicine.


     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].


     G. D'Annunzio University School of Pharmacy.

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