8-Methoxypsoralen is a competitive inhibitor of glutathioneS-transferase P1-1
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , |
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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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 |
format |
article |
status_str |
publishedVersion |
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 |
eu_rights_str_mv |
openAccess |
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 |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UFBA instname:Universidade Federal da Bahia (UFBA) instacron:UFBA |
instname_str |
Universidade Federal da Bahia (UFBA) |
instacron_str |
UFBA |
institution |
UFBA |
reponame_str |
Repositório Institucional da UFBA |
collection |
Repositório Institucional da UFBA |
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