Doxorubicin metabolism and toxicity in human myocardium: Role of cytoplasmic deglycosidation and carbonyl reduction

The anthracycline doxolubicin (DOX) is an exceptionally good antineoplastic agent, but its use is limited by formation of metabolites which induce acu te 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 rea ctivity of toxic metabolites in humans; therefore, we used an ethically acc eptable system which is suitable for exploring DOX metabolism in human myoc ardium. The system involves cytosolic fractions from myocardial samples obt ained during aorto-coronary bypass grafting. After reconstitution with NADP H and DOX, these fractions generate the alcohol metabolite doxorubicinol (D OXol) as well as DOX deoxyaglycone and DOXol hydroxyaglycone, reflecting re duction 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 e valuated 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 hydroxy aglycone but decrease that of DOXol. Conversely, high DOX:protein ratios fa cilitate the formation of DOXol but impair reductase- or hydrolase-type deg lycosidation and uncouple hydrolysis from carbonyl reduction, making DOXol accumulate at levels higher than those of DOX deoxyaglycone and DOXol hydro xyaglycone. Structure-activity considerations have suggested that aglycones and DOXol may inflict cardiac damage by inducing oxidative stress or by pe rturbing 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 activit y of aglycones, whereas the life-threatening chronic toxicity should be att ributed to alterations of iron homeostasis by DOXol. This picture rationali zes the limited protective efficacy of antioxidants against chronic cardiom yopathy vis-a-vis the better protection offered by iron chelators, and form s the basis for developing analogues which produce less DOXol.