Peroxidase- and Nitrite-Dependent Metabolism of the Anthracycline Anticancer Agents Daunorubicin and Doxorubicin

• Published in: Biochemistry (Easton) 2001-12, Vol.40 (50), p.15349-15361
• Main Authors: Reszka, Krzysztof J, McCormick, Michael L, Britigan, Bradley E
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Daunorubicin - adverse effects; Daunorubicin - chemistry; Daunorubicin - metabolism; Doxorubicin - adverse effects; Doxorubicin - chemistry; Doxorubicin - metabolism; Electron Spin Resonance Spectroscopy; Horseradish Peroxidase - metabolism; Humans; Hydrogen Peroxide - metabolism; Hydrogen-Ion Concentration; Lactoperoxidase - metabolism; Nitrites - metabolism; Oxidation-Reduction; Spectrophotometry
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi011869c

Oxidation of the anticancer anthracyclines doxorubicin (DXR) and daunorubicin (DNR) by lactoperoxidase(LPO)/H2O2 and horseradish peroxidase(HRP)/H2O2 systems in the presence and absence of nitrite (NO2 -) has been investigated using spectrophotometric and EPR techniques. We report that LPO/H2O2/NO2 - causes rapid and irreversible loss of anthracyclines' absorption bands, suggesting oxidative degradation of their chromophores. Both the initial rate and the extent of oxidation are dependent on both NO2 - concentration and pH. The initial rate decreases when the pH is changed from 7 to 5, and the reaction virtually stops at pH 5. Oxidation of a model hydroquinone compound, 2,5-di-tert-butylhydroquinone, by LPO/H2O2 is also dependent on NO2 -; however, in contrast to DNR and DXR, this oxidation is most efficient at pH 5, indicating that LPO/H2O2/NO2 - is capable of efficiently oxidizing simple hydroquinones even in the neutral form. Oxidation of anthracyclines by HRP/H2O2/NO2 - is substantially less efficient relative to that by LPO/H2O2/NO2 - at either pH 5 or pH 7, most likely due to the lower rate of NO2 - metabolism by HRP/H2O2. EPR measurements show that interaction of anthracyclines and 2,5-di-tert-butylhydroquinone with LPO/H2O2/NO2 - generates the corresponding semiquinone radicals presumably via one-electron oxidation of their hydroquinone moieties. The possible role of the •NO2 radical, a putative LPO metabolite of NO2 -, in oxidation of these compounds is discussed. Because in vivo the anthracyclines may co-localize with peroxidases, H2O2, and NO2 - in tissues, their oxidation via the proposed mechanism is likely. These observations reveal a novel, peroxidase- and nitrite-dependent mechanism for the oxidative transformation of the anticancer anthracyclines, which may be pertinent to their biological activities in vivo.