Influence of the pro-inflammatory cytokines on P-glycoprotein expression and functionality.
OBJECTIVE
P-glycoprotein (P-gp) is involved in the transport of many drugs at different barriers with consequence in terms of drug distribution and elimination. The expression and activity of P-gp can be modulated by different factors and pathologies. The present article reviews the knowledge regarding the effect of pro-inflammatory cytokines (TNFalpha, IL-1beta, IL-6, IL-2, IFNgamma) on the expression and the functionality of P-gp at three major sites of drug absorption and disposition: the liver, the blood-brain barrier, and the intestine.


METHODS
The various methods used to study the effect of pro-inflammatory cytokines include in vivo models (i.e. animals infected with Staphylococcus sp, animals injected with bacterial lipopolysaccharide or directly with cytokines, ...) and in vitro models (i.e. primary rat hepatocytes, human brain endothelial cells, ...).


RESULTS
The data on P-gp expression and/or function may differ according to the compound used to induce inflammation. However, there is a general trend towards a decrease in both the expression of P-gp (mRNA and protein) and its functionality. Transcription factors and nuclear receptors are probably involved in this regulation.


CONCLUSIONS
Cytokines may interfere with P-gp. Hence, in pathological conditions (inflammation, infection, ...), the expression and functionality of P-glycoprotein may be modulated with consequences for drug disposition and, consequently treatment efficacy.
Fernandez
Christine
C
Faculté de Pharmacie, Pharmacie clinique, 5, rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France. christine.fernandez@psl.ap-hop-paris.fr <christine.fernandez@psl.ap-hop-paris.fr>
Buyse
Marion
M
German-Fattal
Michèle
M
Gimenez
François
F
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides; D051381:Rats
D018435:ATP Binding Cassette Transporter, Subfamily B; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D007371:Interferon-gamma