The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes
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 doxor...
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| Format: | Article |
| Language: | English |
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Associação Brasileira de Divulgação Científica
2003-12-01
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| Series: | Brazilian Journal of Medical and Biological Research |
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| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2003001200005 |
| _version_ | 1818015259436253184 |
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| author | F. Misiti B. Giardina A. Mordente M.E. Clementi |
| author_facet | F. Misiti B. Giardina A. Mordente M.E. Clementi |
| author_sort | F. Misiti |
| collection | DOAJ |
| description | 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 37ºC) of intact human red blood cells to doxorubicinol (40 µM) and to aglycone derivatives of doxorubicin (40 µM) 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. |
| first_indexed | 2024-04-14T06:54:35Z |
| format | Article |
| id | doaj.art-b3d9c0edd828480293ebf51f271c327c |
| institution | Directory Open Access Journal |
| issn | 0100-879X 1414-431X |
| language | English |
| last_indexed | 2024-04-14T06:54:35Z |
| publishDate | 2003-12-01 |
| publisher | Associação Brasileira de Divulgação Científica |
| record_format | Article |
| series | Brazilian Journal of Medical and Biological Research |
| spelling | doaj.art-b3d9c0edd828480293ebf51f271c327c2022-12-22T02:06:56ZengAssociação Brasileira de Divulgação CientíficaBrazilian Journal of Medical and Biological Research0100-879X1414-431X2003-12-0136121643165110.1590/S0100-879X2003001200005The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytesF. MisitiB. GiardinaA. MordenteM.E. ClementiAnthracyclines, 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 37ºC) of intact human red blood cells to doxorubicinol (40 µM) and to aglycone derivatives of doxorubicin (40 µM) 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.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2003001200005AnthracyclinesDoxorubicinolDoxorubicinAglycone metabolitePentose phosphate pathway[13C]-NMR spectroscopyHemoglobin |
| spellingShingle | F. Misiti B. Giardina A. Mordente M.E. Clementi The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes Brazilian Journal of Medical and Biological Research Anthracyclines Doxorubicinol Doxorubicin Aglycone metabolite Pentose phosphate pathway [13C]-NMR spectroscopy Hemoglobin |
| title | The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes |
| title_full | The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes |
| title_fullStr | The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes |
| title_full_unstemmed | The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes |
| title_short | The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes |
| title_sort | secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes |
| topic | Anthracyclines Doxorubicinol Doxorubicin Aglycone metabolite Pentose phosphate pathway [13C]-NMR spectroscopy Hemoglobin |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2003001200005 |
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