The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes

• Published in: Brazilian journal of medical and biological research Vol. 36; no. 12; pp. 1643 - 1651
• Main Authors: Misiti, F, Giardina, B, Mordente, A, Clementi, M E
• Format: Journal Article
• Language: English; Portuguese
• Published: Brazil Associação Brasileira de Divulgação Científica 01.12.2003
• Subjects: [13C]-NMR spectroscopy; Aglycone metabolite; Anthracyclines; Antibiotics, Antineoplastic - pharmacology; BIOLOGY; Doxorubicin; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacology; Doxorubicinol; Erythrocytes - drug effects; Erythrocytes - enzymology; Hemoglobin; Humans; Magnetic Resonance Spectroscopy; MEDICINE, RESEARCH & EXPERIMENTAL; Pentose phosphate pathway; Pentose Phosphate Pathway - drug effects; [13C]-NMR spectroscopy; Anthracyclines; Pentose phosphate pathway; Hemoglobin; Aglycone metabolite; Doxorubicin; Doxorubicinol
• ISSN: 0100-879X; 1414-431X; 1414-431X; 0100-879X
• DOI: 10.1590/S0100-879X2003001200005

Anthracyclines, a class of antitumor drugs widely used for the treatment of solid and hematological malignancies, cause a cumulative dose-dependent cardiac toxicity whose biochemical basis is unclear. Recent studies of the role of the metabolites of anthracyclines, i.e., the alcohol metabolite doxorubicinol and aglycone metabolites, have suggested new hypotheses about the mechanisms of anthracycline cardiotoxicity. In the present study, human red blood cells were used as a cell model. Exposure (1 h at 37 C) of intact human red blood cells to doxorubicinol (40 M) and to aglycone derivatives of doxorubicin (40 M) induced, compared with untreated red cells: i) a ~2-fold stimulation of the pentose phosphate pathway (PPP) and ii) a marked inhibition of the red cell antioxidant enzymes, glutathione peroxidase (~20%) and superoxide dismutase (~60%). In contrast to doxorubicin-derived metabolites, doxorubicin itself induced a slighter PPP stimulation (~35%) and this metabolic event was not associated with any alteration in glutathione reductase, glutathione peroxidase, catalase or superoxide dismutase activity. Furthermore, the interaction of hemoglobin with doxorubicin and its metabolites induced a significant increase (~22%) in oxygen affinity compared with hemoglobin incubated without drugs. On the basis of the results obtained in the present study, a new hypothesis, involving doxorubicinol and aglycone metabolites, has been proposed to clarify the mechanisms responsible for the doxorubicin-induced red blood cell toxicity.