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

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• 作者：Sabrina Licata ; Antonella Saponiero ; Alvaro Mordente ; and Giorgio Minotti
• 刊名：Chemical Research in Toxicology
• 出版年：2000
• 出版时间：May 2000
• 年：2000
• 卷：13
• 期：5
• 页码：414 - 420
• 全文大小：73K
• 年卷期：v.13,no.5(May 2000)
• ISSN：1520-5010

文摘

The anthracycline doxorubicin (DOX) is an exceptionally good antineoplastic agent, but itsuse 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-threateningcardiomyopathy. Studies in laboratory animals are of limited value in predicting the structureand reactivity of toxic metabolites in humans; therefore, we used an ethically acceptable systemwhich is suitable for exploring DOX metabolism in human myocardium. The system involvescytosolic fractions from myocardial samples obtained during aorto-coronary bypass grafting.After reconstitution with NADPH and DOX, these fractions generate the alcohol metabolitedoxorubicinol (DOXol) as well as DOX deoxyaglycone and DOXol hydroxyaglycone, reflectingreduction of the side chain carbonyl group, reductase-type deglycosidation of the anthracycline,and hydrolase-type deglycosidation followed by carbonyl reduction, respectively. The efficiencyof each metabolic route has been evaluated at low and high DOX:protein ratios, reproducingacute, single-dose and chronic, multiple-dose regimens, respectively. Low DOX:protein ratiosincrease the efficiency of formation of DOX deoxyaglycone and DOXol hydroxyaglycone butdecrease that of DOXol. Conversely, high DOX:protein ratios facilitate the formation of DOXolbut impair reductase- or hydrolase-type deglycosidation and uncouple hydrolysis from carbonylreduction, making DOXol accumulate at levels higher than those of DOX deoxyaglycone andDOXol hydroxyaglycone. Structure-activity considerations have suggested that aglycones andDOXol may inflict cardiac damage by inducing oxidative stress or by perturbing ironhomeostasis, respectively. Having characterized the influence of DOX:protein ratios ondeglycosidation or carbonyl reduction, we propose that the benign acute toxicity should beattributed to the oxidant activity of aglycones, whereas the life-threatening chronic toxicityshould be attributed to alterations of iron homeostasis by DOXol. This picture rationalizesthe limited protective efficacy of antioxidants against chronic cardiomyopathy vis-à-vis thebetter protection offered by iron chelators, and forms the basis for developing analogues whichproduce less DOXol.