Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen

Detalhes bibliográficos
Autor(a) principal: Cardoso, Carla M. P.
Data de Publicação: 2003
Outros Autores: Moreno, António J. M., Almeida, Leonor M., Custódio, José 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/10316/5778
https://doi.org/10.1016/S0887-2333(03)00106-1
Resumo: The antiestrogen tamoxifen (TAM) inhibits the growth of different estrogen receptor (ER)-negative cells. Recently, multiple effects of TAM on mitochondrial bioenergetic functions have been pointed to explain its ER-independent cell death mechanisms. We have shown that TAM and its major active metabolite 4-hydroxytamoxifen (OHTAM) induce depolarization of the mitochondrial membrane potential ([Delta][Psi]) and uncouple the mitochondrial respiration, depressing the oxidative phosphorylation efficiency. To clarify the biochemical mechanisms underlying the changes in the regulation of ATP synthesis and yield, in this work we evaluated the alterations of mitochondrial adenine nucleotides induced by both drugs and ascertained whether such changes could reflect a specific inhibition of either the adenine nucleotide translocase (ANT) or the phosphate carrier, as well as the activation of ATP hydrolysis due to [Delta][Psi] depolarization. We found that both antiestrogens caused a concentration-dependent decrease in mitochondrial ATP levels. Mitochondrial ADP and AMP were concomitantly increased with a subsequent decrease in the ATP/ADP or ATP/AMP ratios. The total concentration of adenine nucleotides also changed. Additionally, both drugs decreased the ANT content of mitochondria, inhibited the phosphate carrier and induced ATP hydrolysis. However, the effects of TAM were more drastic than those induced by OHTAM. Therefore, the depletion of ATP might result from an activation of ATP catabolism, as well as from a decrease in the mitochondrial content of ANT and partial inhibition of the phosphate carrier. Our data may explain the ER-independent effects and cytotoxicity of both drugs and, in agreement with other previous studies, suggest that OHTAM is much less toxic to mitochondria than TAM.
id RCAP_409571e5f93279f44c9e8745af87909d
oai_identifier_str oai:estudogeral.uc.pt:10316/5778
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen4-HydroxytamoxifenMitochondrial energeticsMitochondrial adenine nucleotidesPhosphate carrierAdenine nucleotide translocaseTamoxifenThe antiestrogen tamoxifen (TAM) inhibits the growth of different estrogen receptor (ER)-negative cells. Recently, multiple effects of TAM on mitochondrial bioenergetic functions have been pointed to explain its ER-independent cell death mechanisms. We have shown that TAM and its major active metabolite 4-hydroxytamoxifen (OHTAM) induce depolarization of the mitochondrial membrane potential ([Delta][Psi]) and uncouple the mitochondrial respiration, depressing the oxidative phosphorylation efficiency. To clarify the biochemical mechanisms underlying the changes in the regulation of ATP synthesis and yield, in this work we evaluated the alterations of mitochondrial adenine nucleotides induced by both drugs and ascertained whether such changes could reflect a specific inhibition of either the adenine nucleotide translocase (ANT) or the phosphate carrier, as well as the activation of ATP hydrolysis due to [Delta][Psi] depolarization. We found that both antiestrogens caused a concentration-dependent decrease in mitochondrial ATP levels. Mitochondrial ADP and AMP were concomitantly increased with a subsequent decrease in the ATP/ADP or ATP/AMP ratios. The total concentration of adenine nucleotides also changed. Additionally, both drugs decreased the ANT content of mitochondria, inhibited the phosphate carrier and induced ATP hydrolysis. However, the effects of TAM were more drastic than those induced by OHTAM. Therefore, the depletion of ATP might result from an activation of ATP catabolism, as well as from a decrease in the mitochondrial content of ANT and partial inhibition of the phosphate carrier. Our data may explain the ER-independent effects and cytotoxicity of both drugs and, in agreement with other previous studies, suggest that OHTAM is much less toxic to mitochondria than TAM.http://www.sciencedirect.com/science/article/B6TCP-49C5CK6-6/1/f5b08afedd3f5563da8601805f04bc8f2003info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5778http://hdl.handle.net/10316/5778https://doi.org/10.1016/S0887-2333(03)00106-1engToxicology in Vitro. 17:5-6 (2003) 663-670Cardoso, Carla M. P.Moreno, António J. M.Almeida, Leonor M.Custódio, José 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:RCAAP2020-11-06T16:59:52Zoai:estudogeral.uc.pt:10316/5778Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:18.094618Repositório 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 Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
title Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
spellingShingle Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
Cardoso, Carla M. P.
4-Hydroxytamoxifen
Mitochondrial energetics
Mitochondrial adenine nucleotides
Phosphate carrier
Adenine nucleotide translocase
Tamoxifen
title_short Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
title_full Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
title_fullStr Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
title_full_unstemmed Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
title_sort Comparison of the changes in adenine nucleotides of rat liver mitochondria induced by tamoxifen and 4-hydroxytamoxifen
author Cardoso, Carla M. P.
author_facet Cardoso, Carla M. P.
Moreno, António J. M.
Almeida, Leonor M.
Custódio, José B. A.
author_role author
author2 Moreno, António J. M.
Almeida, Leonor M.
Custódio, José B. A.
author2_role author
author
author
dc.contributor.author.fl_str_mv Cardoso, Carla M. P.
Moreno, António J. M.
Almeida, Leonor M.
Custódio, José B. A.
dc.subject.por.fl_str_mv 4-Hydroxytamoxifen
Mitochondrial energetics
Mitochondrial adenine nucleotides
Phosphate carrier
Adenine nucleotide translocase
Tamoxifen
topic 4-Hydroxytamoxifen
Mitochondrial energetics
Mitochondrial adenine nucleotides
Phosphate carrier
Adenine nucleotide translocase
Tamoxifen
description The antiestrogen tamoxifen (TAM) inhibits the growth of different estrogen receptor (ER)-negative cells. Recently, multiple effects of TAM on mitochondrial bioenergetic functions have been pointed to explain its ER-independent cell death mechanisms. We have shown that TAM and its major active metabolite 4-hydroxytamoxifen (OHTAM) induce depolarization of the mitochondrial membrane potential ([Delta][Psi]) and uncouple the mitochondrial respiration, depressing the oxidative phosphorylation efficiency. To clarify the biochemical mechanisms underlying the changes in the regulation of ATP synthesis and yield, in this work we evaluated the alterations of mitochondrial adenine nucleotides induced by both drugs and ascertained whether such changes could reflect a specific inhibition of either the adenine nucleotide translocase (ANT) or the phosphate carrier, as well as the activation of ATP hydrolysis due to [Delta][Psi] depolarization. We found that both antiestrogens caused a concentration-dependent decrease in mitochondrial ATP levels. Mitochondrial ADP and AMP were concomitantly increased with a subsequent decrease in the ATP/ADP or ATP/AMP ratios. The total concentration of adenine nucleotides also changed. Additionally, both drugs decreased the ANT content of mitochondria, inhibited the phosphate carrier and induced ATP hydrolysis. However, the effects of TAM were more drastic than those induced by OHTAM. Therefore, the depletion of ATP might result from an activation of ATP catabolism, as well as from a decrease in the mitochondrial content of ANT and partial inhibition of the phosphate carrier. Our data may explain the ER-independent effects and cytotoxicity of both drugs and, in agreement with other previous studies, suggest that OHTAM is much less toxic to mitochondria than TAM.
publishDate 2003
dc.date.none.fl_str_mv 2003
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/5778
http://hdl.handle.net/10316/5778
https://doi.org/10.1016/S0887-2333(03)00106-1
url http://hdl.handle.net/10316/5778
https://doi.org/10.1016/S0887-2333(03)00106-1
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Toxicology in Vitro. 17:5-6 (2003) 663-670
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv aplication/PDF
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
_version_ 1799133750530932736