Carbonyl Reduction of Daunorubicin in Rabbit Liver and Heart

Abstract

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@) 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.

Carbonyl Reductases and Pluripotent Hydroxysteroid Dehydrogenases of the Short-chain Dehydrogenase/reductase Superfamily

“…As previously stated, prevention of carbonyl reduction may represent a potential approach to enhancing the safety and efficiency of cytostatics in clinical chemotherapy (Propper and Maser, 1997). This could be achieved either by inhibiting the enzymes responsible for drug inactivation or by chemically modifying the chemotherapeutic molecule such that it loses its affinity for the inactivating enzymes.…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…Inhibitors of AKR1C enzymes have been found to be ineffective in inhibiting reduction of either daunorubicin or doxorubicin, suggesting that AKR1C proteins do not play a major role in their metabolism. In contrast to the human myocardium, in the rabbit heart carbonyl reductases have been found to play a major role in the reduction of both of these drugs, underscoring the danger of extrapolating preclinical results obtained in animal models to human patients (Propper and Maser, 1997;Kaiserova and Kvasnickova, 2005;Mordente et al, 2003).…”

Carbonyl reductase 1 as a novel target of (−)‐epigallocatechin gallate against hepatocellular carcinoma†

“…Because of CBR1's role in the resistance to and toxicity of anthracyclines, it has been speculated that the inhibition of CBR1 to prevent carbonyl reduction may be an effective approach to enhancing the efficiency and reducing the toxicity of anthracyclines 17. In the SDR family, several enzymes are sensitive to inhibition by flavonoids, a group of natural products of plant origin.…”