Document Detail


In vitro study of P-glycoprotein induction as an antidotal pathway to prevent cytotoxicity in Caco-2 cells.
MedLine Citation:
PMID:  20857089     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
The Caco-2 cell line is a reliable in vitro model for predicting drug intestinal absorption and P-glycoprotein (P-gp)-mediated excretion in humans. Recent in vivo studies suggested the induction of P-gp as a cellular protection tool against paraquat poisoning, through the increase in its pulmonary and intestinal excretion. Thus, the aim of the present work was to evaluate P-gp expression and activity in Caco-2 cells exposed to doxorubicin (a known P-gp inducer) and to correlate these changes with paraquat toxic effects. Cytotoxicity of doxorubicin (0-100 μM) and paraquat (0-1,000 μM) was evaluated for a maximum period of 96 h. In doxorubicin-exposed cells, P-gp expression and transport activity were evaluated by flow cytometry, using a fluorescein isothiocyanate-conjugated antibody and the P-gp fluorescent subtract rhodamine 123, respectively. A significant increase in P-gp expression was observed as soon as 6 h after exposure to 5 μM doxorubicin. P-gp activity also increased after 6 h, but only at higher doxorubicin concentrations (over 50 μM). Paraquat (0-5,000 μM) cytotoxicity was then evaluated with or without previous exposure of the cells to doxorubicin (5-100 μM, a concentration range causing both an increase in P-gp expression and activity). Under P-gp induction, a significant reduction in paraquat cytotoxicity was observed. Furthermore, when these cells were incubated with a specific P-gp inhibitor (UIC2 antibody) the doxorubicin protective effects were blocked, confirming the involvement of P-gp in the reduction in paraquat cytotoxicity. In conclusion, the human Caco-2 cell line model can be used for the study of P-gp induction as an antidotal pathway against substrates of this transporter system.
Authors:
Renata Silva; Helena Carmo; Ricardo Dinis-Oliveira; Anabela Cordeiro-da-Silva; Sofia Costa Lima; Félix Carvalho; Maria de Lourdes Bastos; Fernando Remião
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Publication Detail:
Type:  Journal Article     Date:  2010-09-21
Journal Detail:
Title:  Archives of toxicology     Volume:  85     ISSN:  1432-0738     ISO Abbreviation:  Arch. Toxicol.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-03-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0417615     Medline TA:  Arch Toxicol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  315-26     Citation Subset:  IM    
Affiliation:
REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha, 164, 4099-030, Porto, Portugal, rsilva@ff.up.pt.
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