8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1

Detalhes bibliográficos
Autor(a) principal: Oliveira, Diêgo Madureira de
Data de Publicação: 2014
Outros Autores: Farias, Marcel Tavares de, Teles, André Lacerda Braga, Santos Junior, Manoelito Coelho dos, Cerqueira, Martins Dias de, Lima, Rute Maria Ferreira, El-Bachá, Ramon dos Santos
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UFBA
Texto Completo: http://repositorio.ufba.br/ri/handle/ri/20742
Resumo: The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8-MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8-MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy.
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spelling Oliveira, Diêgo Madureira deFarias, Marcel Tavares deTeles, André Lacerda BragaSantos Junior, Manoelito Coelho dosCerqueira, Martins Dias deLima, Rute Maria FerreiraEl-Bachá, Ramon dos SantosOliveira, Diêgo Madureira deFarias, Marcel Tavares deTeles, André Lacerda BragaSantos Junior, Manoelito Coelho dosCerqueira, Martins Dias deLima, Rute Maria FerreiraEl-Bachá, Ramon dos Santos2016-10-06T13:28:03Z2016-10-06T13:28:03Z2014-09-30Oliveira, et al... 20141664-8714http://repositorio.ufba.br/ri/handle/ri/20742V. 8The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8-MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8-MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy.Submitted by Ramon El-Bachá (ramon@ufba.br) on 2016-09-30T21:14:52Z No. of bitstreams: 2 de Oliveira et al 2014.pdf: 4502740 bytes, checksum: 11bb6de41dab58b178540d7eb8540bfc (MD5) de Oliveira et al 2014 Suppl Data.pdf: 753271 bytes, checksum: e47bc2ad64a11181973205f41f2c061c (MD5)Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2016-10-06T13:28:03Z (GMT) No. of bitstreams: 2 de Oliveira et al 2014.pdf: 4502740 bytes, checksum: 11bb6de41dab58b178540d7eb8540bfc (MD5) de Oliveira et al 2014 Suppl Data.pdf: 753271 bytes, checksum: e47bc2ad64a11181973205f41f2c061c (MD5)Made available in DSpace on 2016-10-06T13:28:03Z (GMT). No. of bitstreams: 2 de Oliveira et al 2014.pdf: 4502740 bytes, checksum: 11bb6de41dab58b178540d7eb8540bfc (MD5) de Oliveira et al 2014 Suppl Data.pdf: 753271 bytes, checksum: e47bc2ad64a11181973205f41f2c061c (MD5) Previous issue date: 2014-09-30CNPq/BNBFrontiers in Cellular NeuroscienceBrasilhttp://journal.frontiersin.org/article/10.3389/fncel.2014.00308/fullreponame:Repositório Institucional da UFBAinstname:Universidade Federal da Bahia (UFBA)instacron:UFBAGST8-MOPglioblastoma8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessengORIGINALde Oliveira et al 2014.pdfde Oliveira et al 2014.pdfArtigo principalapplication/pdf4502740https://repositorio.ufba.br/bitstream/ri/20742/1/de%20Oliveira%20et%20al%202014.pdf11bb6de41dab58b178540d7eb8540bfcMD51de Oliveira et al 2014 Suppl Data.pdfde Oliveira et al 2014 Suppl Data.pdfDados suplementaresapplication/pdf753271https://repositorio.ufba.br/bitstream/ri/20742/2/de%20Oliveira%20et%20al%202014%20Suppl%20Data.pdfe47bc2ad64a11181973205f41f2c061cMD52LICENSElicense.txtlicense.txttext/plain1345https://repositorio.ufba.br/bitstream/ri/20742/3/license.txtff6eaa8b858ea317fded99f125f5fcd0MD53TEXTde Oliveira et al 2014.pdf.txtde Oliveira et al 2014.pdf.txtExtracted texttext/plain52727https://repositorio.ufba.br/bitstream/ri/20742/4/de%20Oliveira%20et%20al%202014.pdf.txt3ca2dafc84521f5c27767090eb9dd4beMD54de Oliveira et al 2014 Suppl Data.pdf.txtde Oliveira et al 2014 Suppl Data.pdf.txtExtracted texttext/plain5349https://repositorio.ufba.br/bitstream/ri/20742/5/de%20Oliveira%20et%20al%202014%20Suppl%20Data.pdf.txt4da5af2dd33a8b425866f3203ffacb61MD55ri/207422022-07-05 14:05:17.589oai:repositorio.ufba.br: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Repositório InstitucionalPUBhttp://192.188.11.11:8080/oai/requestopendoar:19322022-07-05T17:05:17Repositório Institucional da UFBA - Universidade Federal da Bahia (UFBA)false
dc.title.pt_BR.fl_str_mv 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
title 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
spellingShingle 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
Oliveira, Diêgo Madureira de
GST
8-MOP
glioblastoma
title_short 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
title_full 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
title_fullStr 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
title_full_unstemmed 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
title_sort 8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
author Oliveira, Diêgo Madureira de
author_facet Oliveira, Diêgo Madureira de
Farias, Marcel Tavares de
Teles, André Lacerda Braga
Santos Junior, Manoelito Coelho dos
Cerqueira, Martins Dias de
Lima, Rute Maria Ferreira
El-Bachá, Ramon dos Santos
author_role author
author2 Farias, Marcel Tavares de
Teles, André Lacerda Braga
Santos Junior, Manoelito Coelho dos
Cerqueira, Martins Dias de
Lima, Rute Maria Ferreira
El-Bachá, Ramon dos Santos
author2_role author
author
author
author
author
author
dc.contributor.author.fl_str_mv Oliveira, Diêgo Madureira de
Farias, Marcel Tavares de
Teles, André Lacerda Braga
Santos Junior, Manoelito Coelho dos
Cerqueira, Martins Dias de
Lima, Rute Maria Ferreira
El-Bachá, Ramon dos Santos
Oliveira, Diêgo Madureira de
Farias, Marcel Tavares de
Teles, André Lacerda Braga
Santos Junior, Manoelito Coelho dos
Cerqueira, Martins Dias de
Lima, Rute Maria Ferreira
El-Bachá, Ramon dos Santos
dc.subject.por.fl_str_mv GST
8-MOP
glioblastoma
topic GST
8-MOP
glioblastoma
description The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8-MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8-MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy.
publishDate 2014
dc.date.issued.fl_str_mv 2014-09-30
dc.date.accessioned.fl_str_mv 2016-10-06T13:28:03Z
dc.date.available.fl_str_mv 2016-10-06T13:28:03Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.citation.fl_str_mv Oliveira, et al... 2014
dc.identifier.uri.fl_str_mv http://repositorio.ufba.br/ri/handle/ri/20742
dc.identifier.issn.none.fl_str_mv 1664-8714
dc.identifier.number.pt_BR.fl_str_mv V. 8
identifier_str_mv Oliveira, et al... 2014
1664-8714
V. 8
url http://repositorio.ufba.br/ri/handle/ri/20742
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Frontiers in Cellular Neuroscience
dc.publisher.country.fl_str_mv Brasil
publisher.none.fl_str_mv Frontiers in Cellular Neuroscience
dc.source.pt_BR.fl_str_mv http://journal.frontiersin.org/article/10.3389/fncel.2014.00308/full
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