engleski

Multidrug resistance in inflammatory bowel disease. Expression profiles of MDR1 and MRP1 along gastrointestinal tract

Background and aims: 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. Current medical guidelines recommend orally administered glucocorticoids, antibiotics and immunosuppressants. Glucocorticoids remain the mainstay of treatment for acute exacerbations. However, up to 20 % of patients will fail to respond. Multidrug resistance (MDR) remains one of the primary causes of suboptimal outcomes in therapy. ATP-binding cassete (ABC) transporters are critical components of intestinal barrier function and poor response to therapy and their increased expression or activity contributes to MDR. The mdr genes code for ABC transporters MDR1/ P-glycoprotein (Pgp) and multidrug resistance protein1 (MRP1), drug efflux pumps expressed on the surface of intestinal epithel where they are involved in epithelial membrane integrity and orally administered drug absorption, tissue distribution and detoxification. In the human gastrointestinal tract Pgp is found in high concentrations on the apical surfaces of epithelial cells. Because amplified efflux of orally administered drugs reduces it's bioavailability and because glucocorticoids are supstrates of MDR1/Pgp we set to assess the expression profiles of Pgp and MRP1 at 6 different locations (terminal ileum, ascending, transverse and descending colon, sigma and rectum) of the gastrointestinal tract (GIT). Longitudinal follow up of same patients could explain their potential relevance and impact on treatment response along GIT. Materials and methods: Intestinal biopsy specimens were collected from 22 subjects upon their informed consent in writing, according to the Helsinki Declaration and approved by the Hospital Ethics Committees. All patients were newly diagnosed. Total RNA was extracted from more than 130 intestinal biopsy specimens, a total of 15 IBD (11 CD, mean age 38 years and 4 UC, mean age 51 years) and 7 age and sex-matched healthy controls.Gene expression was investigated by quantitative real-time PCR (TaqMan). The outcome of the first treatment course was studied in one patient after 3 months. Results: There is regional variation of ABC transporters in gastrointestinal tract, but in general localization did not differ between IBD patients and controls. MRP1 expression was constant at all 6 locations. Pgp is maximally expressed within the small intestine with a gradual decrease proximally into the colon. The highest mdr1 expression was found on terminal ileum, then it droped and stayed approximately the same in the colon with lowest level of expression in rectum. Furthermore, high mdr1 gene expression (0, 86+/-2) in CD was still significantly (p<0.05) lower compared to control (0, 93+/-1) samples. In all segments of the colon the expression level of mdr1 was higher than mrp1. After three months of immunosuppressive therapy and partial remission, Pgp is found to be considerably lower in comparison to pretreatment data but still in highest expression profiles on terminal ileum. Conclusions: Lower expression of both transporters in CD can be the result of inflamation proces and possible altered interaction with local microenviroment. These results do not exclude the posibility that increased expression of transporters contribute to MDR (because all CD patients were newly diagnosed). It will be interessant to follow up those patients with lower pre-treatment values to check the hypothesis.

MDR; Pgp; MRP; IBD; CD; RT PCR

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