8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1
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, biochem...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-09-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00308/full |
| _version_ | 1811232405996961792 |
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| author | Diêgo Madureira Oliveira Marcel Tavares Farias André Lacerda Braga Teles Manoelito Coelho Santos Junior Martins Dias Cerqueira Rute Maria Ferreira Lima Ramon Santos El-Bachá |
| author_facet | Diêgo Madureira Oliveira Marcel Tavares Farias André Lacerda Braga Teles Manoelito Coelho Santos Junior Martins Dias Cerqueira Rute Maria Ferreira Lima Ramon Santos El-Bachá |
| author_sort | Diêgo Madureira Oliveira |
| collection | DOAJ |
| 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 catalysed 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. |
| first_indexed | 2024-04-12T11:02:40Z |
| format | Article |
| id | doaj.art-b9bca14d4d1a44dfa2f9086eb4746ef8 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-12T11:02:40Z |
| publishDate | 2014-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-b9bca14d4d1a44dfa2f9086eb4746ef82022-12-22T03:35:55ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022014-09-01810.3389/fncel.2014.003081033908-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1Diêgo Madureira Oliveira0Marcel Tavares Farias1André Lacerda Braga Teles2Manoelito Coelho Santos Junior3Martins Dias Cerqueira4Rute Maria Ferreira Lima5Ramon Santos El-Bachá6University of BrasiliaSão Rafael HospitalState University of Feira de SantanaState University of Feira de SantanaFederal University of BahiaFederal University of BahiaFederal University of BahiaThe 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 catalysed 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.http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00308/fullGlioblastomaCancerGSTBBB8-MOP |
| spellingShingle | Diêgo Madureira Oliveira Marcel Tavares Farias André Lacerda Braga Teles Manoelito Coelho Santos Junior Martins Dias Cerqueira Rute Maria Ferreira Lima Ramon Santos El-Bachá 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1 Frontiers in Cellular Neuroscience Glioblastoma Cancer GST BBB 8-MOP |
| title | 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1 |
| title_full | 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1 |
| title_fullStr | 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1 |
| title_full_unstemmed | 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1 |
| title_short | 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1 |
| title_sort | 8 methoxypsoralen is a competitive inhibitor of glutathione s transferase p1 1 |
| topic | Glioblastoma Cancer GST BBB 8-MOP |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00308/full |
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