Carbonyl reduction of daunorubicin in rabbit liver and heart.
A major problem of anthracycline anticancer treatment are the cardiotoxic side effects associated with drug therapy. Increased attention has recently been focused on the 13-hydroxy anthracycline metabolites which are formed by carbonyl reduction of the parent drug as contributing to cardiotoxicity. By using daunorubicin as a reference molecule, our study was designed to quantitatively evaluate and compare the extent of anthracycline carbonyl reduction of liver and heart at the physiological important pH 7.4, and to identify the enzyme(s) involved under these conditions. The present kinetic data indicate that only one single enzyme system is active in cytosol of both tissues. According to its specific inhibition by quercitrin and the failure of a barbiturate to affect activity the enzyme responsible for daunorubicin carbonyl reduction in these fractions is carbonyl reductase (EC 1.1.1.184). Since the KM values differ significantly from each other, it is suggested that liver and heart express different isoforms of this enzyme. We failed to detect any specific daunorubicin carbonyl reductase activity in both microsomal fractions. Intrinsic clearance values revealed that liver has obviously 350-times the capacity of total 13-hydroxy metabolite formation compared to heart. This indicates that under a therapeutic regimen 13-hydroxy anthracyclines of hepatic origin would add to the metabolites that are produced by the heart itself. The prevention of these metabolites may represent a potential approach for enhancing the safety and efficacy of anthracycline chemotherapy.
Pröpper
D
D
Department of Pharmacology and Toxicology, School of Medicine, Philipps-University of Marburg, Marburg/Lahn, Germany.
Maser
E
E
D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D003630:Daunorubicin / Q000378:metabolism*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D011817:Rabbits
D000903:Antibiotics, Antineoplastic; D000429:Alcohol Oxidoreductases; D003630:Daunorubicin