title: Cyclooxygenase-2 inhibitors prevent trinitrobenzene sulfonic acid-induced P-glycoprotein up-regulation in vitro and in vivo.
abstract: Failed medical therapy is a common problem in inflammatory bowel disease. P-glycoprotein (P-gp), an efflux pump encoded by MDR1 (ABCB1) gene can actively pump drugs out of cells conferring the phenotype of multidrug resistance. Various studies evoked that cyclooxygenase (COX) system may be involved in the regulation of P-gp activity. Since COX-2 isoform is overexpressed in colic inflammatory states, we examined the inhibitory effect of COX-2-inhibitors on P-gp expression and function under COX-2 stimulated conditions mediated by trinitrobenzene sulfonic acid (TNBS) in vitro, in Caco-2 cells, and in TNBS-induced colitis in mice. COX-2 and P-gp expressions were evaluated by real-time PCR and western blot. The activity of P-gp was measured by intracellular accumulation of rhodamine123 (Rho123) in Caco-2 cells and by Rho123 efflux using the intestinal everted loop method in mice. We showed that COX-2 stimulation in Caco-2 cells by 0.1mM TNBS exposure for 24h induced P-gp protein expression and activity. This activation was reversed by simultaneous COX-2-inhibitor treatment. Moreover, this effect was reproduced in vivo, in mice, where an increased P-gp expression and activity were observed 24h post intra-rectal TNBS administration. Induced P-gp expression and activity could be blocked by the oral pre-treatment with indomethacin heptyl ester (IHE) (20mg/kg). Administration of indomethacin heptyl ester had also a protective effect in TNBS-induced colitis. Our observations suggest that the inhibition of P-gp by COX-2-inhibitors could contribute to the improvement of medical response and this finding may have relevance to medical treatment of inflammatory bowel disease patients.
authors.affiliation: Université Paris-Sud XI, Faculté de pharmacie, Laboratoire de Pharmacie Clinique, UPRES EA 2706, Tour D1, 5 rue Jean-Baptist Clément, Châtenay-Malabry 92296, France. afraa.zrieki@u-psud.fr
authors.forename: Afraa
authors.initials: A
authors.lastname: Zrieki
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Marion
authors.initials: M
authors.lastname: Buyse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D052246:Cyclooxygenase 2 Inhibitors; D014302:Trinitrobenzenesulfonic Acid; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D007213:Indomethacin