Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis

Detalhes bibliográficos
Autor(a) principal: Cruz Silva, M. M.
Data de Publicação: 2001
Outros Autores: Madeira, V. M. C., Almeida, L. M., Custódio, J. B. A.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/5795
https://doi.org/10.1016/S0887-2333(01)00079-0
Resumo: 4-Hydroxytamoxifen (OHTAM) is the most active metabolite of the widely prescribed anticancer drug tamoxifen (TAM) used in breast cancer therapy. This work describes the effects of OHTAM on isolated human erythrocytes, using standardized test conditions, to check for a putative contribution to the TAM-induced hemolysis and to study basic mechanisms involved in the interaction of OHTAM with cell membranes. Incubation of isolated human erythrocytes with relatively high concentrations of OHTAM results in a concentration-dependent hemolysis, its hemolytic effect being about one-third of that induced by TAM. OHTAM-induced hemolysis is prevented by either [alpha]-tocopherol ([alpha]-T) or [alpha]-tocopherol acetate ([alpha]-TAc) and it occurs in the absence of oxygen consumption and hemoglobin oxidation, ruling out the oxidative damage of erythrocytes. However, OHTAM remarkably increases the osmotic fragility of erythrocytes, increasing the susceptibility of erythrocytes to hypotonic lysis. Additionally, the hemoglobin release induced by OHTAM is preceded by a rapid efflux of intracellular K+. Therefore, our data suggest that OHTAM-induced hemolysis does not contribute to TAM-induced hemolytic anemia and it is a much weaker toxic drug as compared with TAM. Moreover, at variance with the membrane disrupting effects of TAM, OHTAM promotes perturbation of the membrane's backbone region due to its strong binding to proteins with consequent formation of membrane paths of permeability to small solutes and retention of large solutes like hemoglobin, followed by osmotic swelling and cell lysis. The prevention of OHTAM-induced hemolysis by [alpha]-T and [alpha]-TAc is probably committed to the permeability sealing resulting from structural stabilization of membrane.
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spelling Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis4-HydroxytamoxifenTamoxifenHuman erythrocytesHemolysisOxidative stressOsmotic swelling4-Hydroxytamoxifen (OHTAM) is the most active metabolite of the widely prescribed anticancer drug tamoxifen (TAM) used in breast cancer therapy. This work describes the effects of OHTAM on isolated human erythrocytes, using standardized test conditions, to check for a putative contribution to the TAM-induced hemolysis and to study basic mechanisms involved in the interaction of OHTAM with cell membranes. Incubation of isolated human erythrocytes with relatively high concentrations of OHTAM results in a concentration-dependent hemolysis, its hemolytic effect being about one-third of that induced by TAM. OHTAM-induced hemolysis is prevented by either [alpha]-tocopherol ([alpha]-T) or [alpha]-tocopherol acetate ([alpha]-TAc) and it occurs in the absence of oxygen consumption and hemoglobin oxidation, ruling out the oxidative damage of erythrocytes. However, OHTAM remarkably increases the osmotic fragility of erythrocytes, increasing the susceptibility of erythrocytes to hypotonic lysis. Additionally, the hemoglobin release induced by OHTAM is preceded by a rapid efflux of intracellular K+. Therefore, our data suggest that OHTAM-induced hemolysis does not contribute to TAM-induced hemolytic anemia and it is a much weaker toxic drug as compared with TAM. Moreover, at variance with the membrane disrupting effects of TAM, OHTAM promotes perturbation of the membrane's backbone region due to its strong binding to proteins with consequent formation of membrane paths of permeability to small solutes and retention of large solutes like hemoglobin, followed by osmotic swelling and cell lysis. The prevention of OHTAM-induced hemolysis by [alpha]-T and [alpha]-TAc is probably committed to the permeability sealing resulting from structural stabilization of membrane.http://www.sciencedirect.com/science/article/B6TCP-44B2835-2/1/29f8930b906a9b147f7df74b698fdbbf2001info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5795http://hdl.handle.net/10316/5795https://doi.org/10.1016/S0887-2333(01)00079-0engToxicology in Vitro. 15:6 (2001) 615-622Cruz Silva, M. M.Madeira, V. M. C.Almeida, L. M.Custódio, J. B. A.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2021-09-22T11:40:37Zoai:estudogeral.uc.pt:10316/5795Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:18.499125Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
title Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
spellingShingle Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
Cruz Silva, M. M.
4-Hydroxytamoxifen
Tamoxifen
Human erythrocytes
Hemolysis
Oxidative stress
Osmotic swelling
title_short Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
title_full Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
title_fullStr Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
title_full_unstemmed Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
title_sort Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis
author Cruz Silva, M. M.
author_facet Cruz Silva, M. M.
Madeira, V. M. C.
Almeida, L. M.
Custódio, J. B. A.
author_role author
author2 Madeira, V. M. C.
Almeida, L. M.
Custódio, J. B. A.
author2_role author
author
author
dc.contributor.author.fl_str_mv Cruz Silva, M. M.
Madeira, V. M. C.
Almeida, L. M.
Custódio, J. B. A.
dc.subject.por.fl_str_mv 4-Hydroxytamoxifen
Tamoxifen
Human erythrocytes
Hemolysis
Oxidative stress
Osmotic swelling
topic 4-Hydroxytamoxifen
Tamoxifen
Human erythrocytes
Hemolysis
Oxidative stress
Osmotic swelling
description 4-Hydroxytamoxifen (OHTAM) is the most active metabolite of the widely prescribed anticancer drug tamoxifen (TAM) used in breast cancer therapy. This work describes the effects of OHTAM on isolated human erythrocytes, using standardized test conditions, to check for a putative contribution to the TAM-induced hemolysis and to study basic mechanisms involved in the interaction of OHTAM with cell membranes. Incubation of isolated human erythrocytes with relatively high concentrations of OHTAM results in a concentration-dependent hemolysis, its hemolytic effect being about one-third of that induced by TAM. OHTAM-induced hemolysis is prevented by either [alpha]-tocopherol ([alpha]-T) or [alpha]-tocopherol acetate ([alpha]-TAc) and it occurs in the absence of oxygen consumption and hemoglobin oxidation, ruling out the oxidative damage of erythrocytes. However, OHTAM remarkably increases the osmotic fragility of erythrocytes, increasing the susceptibility of erythrocytes to hypotonic lysis. Additionally, the hemoglobin release induced by OHTAM is preceded by a rapid efflux of intracellular K+. Therefore, our data suggest that OHTAM-induced hemolysis does not contribute to TAM-induced hemolytic anemia and it is a much weaker toxic drug as compared with TAM. Moreover, at variance with the membrane disrupting effects of TAM, OHTAM promotes perturbation of the membrane's backbone region due to its strong binding to proteins with consequent formation of membrane paths of permeability to small solutes and retention of large solutes like hemoglobin, followed by osmotic swelling and cell lysis. The prevention of OHTAM-induced hemolysis by [alpha]-T and [alpha]-TAc is probably committed to the permeability sealing resulting from structural stabilization of membrane.
publishDate 2001
dc.date.none.fl_str_mv 2001
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/5795
http://hdl.handle.net/10316/5795
https://doi.org/10.1016/S0887-2333(01)00079-0
url http://hdl.handle.net/10316/5795
https://doi.org/10.1016/S0887-2333(01)00079-0
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Toxicology in Vitro. 15:6 (2001) 615-622
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