Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate

Detalhes bibliográficos
Autor(a) principal: Custódio, José B. A.
Data de Publicação: 1998
Outros Autores: Moreno, António J. M., Wallace, Kendall B.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/5825
https://doi.org/10.1006/taap.1998.8510
Resumo: Tamoxifen (TAM) is a synthetic, nonsteroidal antiestrogenic agent that is widely prescribed in the treatment of estrogen-dependent neoplasias, including breast cancer. The mechanism of action has yet to be defined, but likely is independent of estrogen receptor binding. In light of its high lipophilicity and peroxyl radical scavenging activities, we hypothesized that TAM might be an effective inhibitor of the mitochondrial permeability transition (MPT), which is widely implicated in the mechanisms of chemical-induced tissue injury and apoptosis. The MPT was inducedin vitroby incubating freshly isolated rat liver mitochondria in 1 mM Pi with increasing concentrations of calcium. Induction of the MPT was characterized by the calcium-dependent depolarization of mitochondrial membrane potential, release of matrix calcium, and large amplitude swelling. Membrane potential and calcium release were measured with ion-selective electrodes; mitochondrial swelling was monitored spectrophotometrically. Preincubation with either cyclosporine A or TAM prevented, in a dose-dependent manner, the calcium-induced MPT. TAM also inhibited the calcium-induced release of matrix glutathione. TAM caused a time-dependent reversal of both the calcium-induced membrane depolarization and calcium release, suggesting that the effect was on the permeability transition pore and not due to inhibition of the mitochondrial calcium uniport. The results suggest that TAM mimics cyclosporine A to inhibit induction of the MPT and that this activity is not related to the antioxidant properties of TAM.
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spelling Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphatetamoxifen; mitochondria; glutathione; permeabilityTamoxifen (TAM) is a synthetic, nonsteroidal antiestrogenic agent that is widely prescribed in the treatment of estrogen-dependent neoplasias, including breast cancer. The mechanism of action has yet to be defined, but likely is independent of estrogen receptor binding. In light of its high lipophilicity and peroxyl radical scavenging activities, we hypothesized that TAM might be an effective inhibitor of the mitochondrial permeability transition (MPT), which is widely implicated in the mechanisms of chemical-induced tissue injury and apoptosis. The MPT was inducedin vitroby incubating freshly isolated rat liver mitochondria in 1 mM Pi with increasing concentrations of calcium. Induction of the MPT was characterized by the calcium-dependent depolarization of mitochondrial membrane potential, release of matrix calcium, and large amplitude swelling. Membrane potential and calcium release were measured with ion-selective electrodes; mitochondrial swelling was monitored spectrophotometrically. Preincubation with either cyclosporine A or TAM prevented, in a dose-dependent manner, the calcium-induced MPT. TAM also inhibited the calcium-induced release of matrix glutathione. TAM caused a time-dependent reversal of both the calcium-induced membrane depolarization and calcium release, suggesting that the effect was on the permeability transition pore and not due to inhibition of the mitochondrial calcium uniport. The results suggest that TAM mimics cyclosporine A to inhibit induction of the MPT and that this activity is not related to the antioxidant properties of TAM.http://www.sciencedirect.com/science/article/B6WXH-45M32S9-15/1/28db6017a9424db5c4c815c3e3ba2e931998info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5825http://hdl.handle.net/10316/5825https://doi.org/10.1006/taap.1998.8510engToxicology and Applied Pharmacology. 152:1 (1998) 10-17Custódio, José B. A.Moreno, António J. M.Wallace, Kendall B.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:RCAAP2020-11-06T16:48:39Zoai:estudogeral.uc.pt:10316/5825Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:24.181448Repositório 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 Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
title Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
spellingShingle Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
Custódio, José B. A.
tamoxifen; mitochondria; glutathione; permeability
title_short Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
title_full Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
title_fullStr Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
title_full_unstemmed Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
title_sort Tamoxifen Inhibits Induction of the Mitochondrial Permeability Transition by Ca2+and Inorganic Phosphate
author Custódio, José B. A.
author_facet Custódio, José B. A.
Moreno, António J. M.
Wallace, Kendall B.
author_role author
author2 Moreno, António J. M.
Wallace, Kendall B.
author2_role author
author
dc.contributor.author.fl_str_mv Custódio, José B. A.
Moreno, António J. M.
Wallace, Kendall B.
dc.subject.por.fl_str_mv tamoxifen; mitochondria; glutathione; permeability
topic tamoxifen; mitochondria; glutathione; permeability
description Tamoxifen (TAM) is a synthetic, nonsteroidal antiestrogenic agent that is widely prescribed in the treatment of estrogen-dependent neoplasias, including breast cancer. The mechanism of action has yet to be defined, but likely is independent of estrogen receptor binding. In light of its high lipophilicity and peroxyl radical scavenging activities, we hypothesized that TAM might be an effective inhibitor of the mitochondrial permeability transition (MPT), which is widely implicated in the mechanisms of chemical-induced tissue injury and apoptosis. The MPT was inducedin vitroby incubating freshly isolated rat liver mitochondria in 1 mM Pi with increasing concentrations of calcium. Induction of the MPT was characterized by the calcium-dependent depolarization of mitochondrial membrane potential, release of matrix calcium, and large amplitude swelling. Membrane potential and calcium release were measured with ion-selective electrodes; mitochondrial swelling was monitored spectrophotometrically. Preincubation with either cyclosporine A or TAM prevented, in a dose-dependent manner, the calcium-induced MPT. TAM also inhibited the calcium-induced release of matrix glutathione. TAM caused a time-dependent reversal of both the calcium-induced membrane depolarization and calcium release, suggesting that the effect was on the permeability transition pore and not due to inhibition of the mitochondrial calcium uniport. The results suggest that TAM mimics cyclosporine A to inhibit induction of the MPT and that this activity is not related to the antioxidant properties of TAM.
publishDate 1998
dc.date.none.fl_str_mv 1998
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/5825
http://hdl.handle.net/10316/5825
https://doi.org/10.1006/taap.1998.8510
url http://hdl.handle.net/10316/5825
https://doi.org/10.1006/taap.1998.8510
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Toxicology and Applied Pharmacology. 152:1 (1998) 10-17
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