Peroxidase- and nitrite-dependent metabolism of the anthracycline anticancer agents daunorubicin and doxorubicin

K. J. Reszka, M. L. McCormick, B. E. Britigan

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15349-15361
Number of pages13
JournalBiochemistry
Volume40
Issue number50
DOIs
StatePublished - Dec 18 2001

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Lactoperoxidase
Daunorubicin
Anthracyclines
Nitrites
Metabolism
Antineoplastic Agents
Doxorubicin
Peroxidase
Oxidation
Horseradish Peroxidase
Paramagnetic resonance
Hydroquinones
Peroxidases
Chromophores
Metabolites
Bioactivity
Absorption spectra
Electrons
Tissue
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Peroxidase- and nitrite-dependent metabolism of the anthracycline anticancer agents daunorubicin and doxorubicin. / Reszka, K. J.; McCormick, M. L.; Britigan, B. E.

In: Biochemistry, Vol. 40, No. 50, 18.12.2001, p. 15349-15361.

Research output: Contribution to journalArticle

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N2 - 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.

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