Peroxidase- and nitrite-dependent metabolism of the anthracycline anticancer agents daunorubicin and doxorubicin.
Oxidation of the anticancer anthracyclines doxorubicin (DXR) and daunorubicin (DNR) by lactoperoxidase(LPO)/H(2)O(2) and horseradish peroxidase(HRP)/H(2)O(2) systems in the presence and absence of nitrite (NO(2)(-)) has been investigated using spectrophotometric and EPR techniques. We report that LPO/H(2)O(2)/NO(2)(-) 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 NO(2)(-) 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/H(2)O(2) is also dependent on NO(2)(-); however, in contrast to DNR and DXR, this oxidation is most efficient at pH 5, indicating that LPO/H(2)O(2)/NO(2)(-) is capable of efficiently oxidizing simple hydroquinones even in the neutral form. Oxidation of anthracyclines by HRP/H(2)O(2)/NO(2)(-) is substantially less efficient relative to that by LPO/H(2)O(2)/NO(2)(-) at either pH 5 or pH 7, most likely due to the lower rate of NO(2)(-) metabolism by HRP/H(2)O(2). EPR measurements show that interaction of anthracyclines and 2,5-di-tert-butylhydroquinone with LPO/H(2)O(2)/NO(2)(-) generates the corresponding semiquinone radicals presumably via one-electron oxidation of their hydroquinone moieties. The possible role of the (*)NO(2) radical, a putative LPO metabolite of NO(2)(-), in oxidation of these compounds is discussed. Because in vivo the anthracyclines may co-localize with peroxidases, H(2)O(2), and NO(2)(-) 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.
Reszka
K J
KJ
Research Service and Department of Internal Medicine, VA Medical Center, University of Iowa, Iowa City, Iowa 52246, USA. reszka@icva.gov
McCormick
M L
ML
Britigan
B E
BE
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D003630:Daunorubicin / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007784:Lactoperoxidase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D013053:Spectrophotometry
D000903:Antibiotics, Antineoplastic; D009573:Nitrites; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D007784:Lactoperoxidase; D003630:Daunorubicin