engleski

Multidrug resistance in inflammatory bowel disease. Localization and expression profiles of ABC transporters Pgp and MRP1 in gastrointestinal tract

Inflammatory bowel disease (IBD) refers to inflamation of small or large intestine and can be manifested in two distinct forms: Ulcerative colitis (UC) and Crohn's disease (CD). Whereas CD is a discontinuous transmural chronic inflammatory disorder that can affect any area of the gastrointestinal tract, the UC is confined to the top layers of the colon and rectum. The exact pathophisiology is unknown but it includes environmental and immunological effects on genetic succeptible individual. Treatment includes antibiotics, anti infflamatory drugs, corticosteroids, immune system supressors and monoclonal antibodyes like Infliximab. Although treatment can lead to remission of the disease a multidrug resistance (MDR) can occur. There are many mechanism that can lead to MDR among which is overexpression of ABC transporters. Because amplified efflux of orally administered drugs reduces it's bioavailability and glucocorticoids are known supstrates of MDR1 (P-glycoprotein, P-gp) we set to assess the expression profiles of P-gp and MRP1 at 6 different locations (terminal ileum, ascending, transverse and descending colon, sigma and rectum) of the gastrointestinal tract (GIT) and in further examinations of same patients see if the treatment leads to increased expression profile of each transporter which could explain the MDR occurence. Materials and methods: Total RNA was extracted from intestinal biopsies of 15 Crohn patients and 7 healthy controls upon their informed consent in writing, according to the Helsinki Declaration and appproved by the Hospital Ethics Committees. All patients were newly diagnosed without any type of cytoreductive treatment prior the study. Gene expression was investigated by quantitative real-time PCR (TaqMan). Results: Both transporters showed higher expression in controls compared to CD, especially at terminal ileum for mdr1 gene (p<0.05). The expression of mdr1 gene was highest at terminal ileum and than droped and remained aproximatelly the same. MRP1 expression was constant at all 6 locations. In all segments of the colon the expression level of mdr1 was higher than mrp1 but reached statistical significance only at terminal ileum (p>0.05). Conclusions: Lower expression of both transporters in CD can be the result of inflamation proces. These results do not exclude the posibility that increased expression of transporters contribute to MDR because all of the CD patients were newly diagnosed. It will be interessant to follow up those patients with lower pre-treatment values to check the hypothesis.

ABC transporters; Pgp; MRP1; IBD; UC; CD; GIT; multidrug resistance

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