title: 8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pathology of Cancer, University of Brasilia Brasilia, Brazil.
authors.forename: Diêgo Madureira
authors.initials: DM
authors.lastname: de Oliveira
authors.affiliation: Laboratory of Clinical and Toxicological Analysis, São Rafael Hospital Salvador, Brazil.
authors.forename: Marcel Tavares
authors.initials: MT
authors.lastname: de Farias
authors.affiliation: Laboratory of Molecular Modeling, State University of Feira de Santana Feira de Santana, Brazil.
authors.forename: André Lacerda Braga
authors.initials: AL
authors.lastname: Teles
authors.affiliation: Laboratory of Molecular Modeling, State University of Feira de Santana Feira de Santana, Brazil.
authors.forename: Manoelito Coelho
authors.initials: MC
authors.lastname: Dos Santos Junior
authors.affiliation: Laboratory of Natural Products, Institute of Chemistry, Federal University of Bahia Salvador, Brazil.
authors.forename: Martins Dias
authors.initials: MD
authors.lastname: de Cerqueira
authors.affiliation: Laboratory of Neurochemistry and Cell Biology, Institute of Health Sciences, Federal University of Bahia Salvador, Brazil.
authors.forename: Rute Maria Ferreira
authors.initials: RM
authors.lastname: Lima
authors.affiliation: Laboratory of Neurochemistry and Cell Biology, Institute of Health Sciences, Federal University of Bahia Salvador, Brazil.
authors.forename: Ramon Santos
authors.initials: RS
authors.lastname: El-Bachá
keywords: 8-MOP; GST; glioblastoma