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Multidrug resistance in inflammatory bowel disease. Pgp and MRP1 expression pattern comparison in the lining of gastrointestinal tract (CROSBI ID 576392)

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Savić, Ana ; Troskot, Branko ; Babić, Žarko ; Bendelja, Krešo ; Svoboda-Beusan, Ivna Multidrug resistance in inflammatory bowel disease. Pgp and MRP1 expression pattern comparison in the lining of gastrointestinal tract // 2011 Annual Meeting of the Croatian Immunological Society, Book of Abstracts. 2011. str. 20-20

Podaci o odgovornosti

Savić, Ana ; Troskot, Branko ; Babić, Žarko ; Bendelja, Krešo ; Svoboda-Beusan, Ivna

engleski

Multidrug resistance in inflammatory bowel disease. Pgp and MRP1 expression pattern comparison in the lining of gastrointestinal tract

Background and aims: Host genetic factors may be important in determining not only disease susceptibility, but also disease behaviour and outcome. Multidrug resistance (MDR) remains one of the primary causes of suboptimal outcomes in therapy. ATP-binding cassette (ABC) transporters are critical components of intestinal barrier function and poor response to therapy. 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. MDR gene polymorphisms, altered expression and amplified function have been associated with predisposition to complex diseases in which environmental and microbial factors play a role. There are controversial data on the association between ABC transporters and inflammatory bowel disease (IBD) which is classified into Crohn’s disease (CD) and ulcerative colitis (UC). UC is manifested as chronic inflammation in the colon and rectum, while CD can affect the whole gastrointestinal tract. Current medical guidelines recommend orally administered glucocorticoids, antibiotics and immunosuppressants. More than 20% of patients with active luminal CD and more than 50% of patients with fistulas fail standard therapy regiment. Glucocorticoids are Pgp/MRP1 substrates and increased expression may result in their reduced bioavailability. As Pgp and MRP1 expression along human intestine has not been studied intensively in IBD as well of their impact on drug bioavailability, the aim of the study was to evaluate their potential relevance and interaction in treatment response within gastrointestinal tract. Materials and methods: Intestinal biopsy specimens from 6 locations (terminal ileum, ascending, transverse and descending colon, sigma and rectum) 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 without any type of cytoreductive treatment prior the study. A total of 15 IBD (11 CD, mean age 38 years and 4 UC, mean age 51 years) and 7 healthy control (mean age 58 years) were evaluated for Pgp and MRP1 expression. Total RNA was extracted from more than 130 intestinal biopsy specimens and gene expression was quantified by real-time PCR (TaqMan). The outcome of the first treatment course was studied in one patient after 3 months of therapy. 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: Decreased expression of ABC transporters in IBD can be the consequence of ongoing inflammatory process and possible altered interaction with local microenviroment in non treated patients. In accordance with the hypothesis that increased expression of transporters contributes to MDR, it will be interesting to follow up those patients with lower pre-treatment values to check whether ABC transporters correlate with clinical symptoms and outcome in IBD.

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

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Podaci o prilogu

20-20.

2011.

objavljeno

Podaci o matičnoj publikaciji

2011 Annual Meeting of the Croatian Immunological Society, Book of Abstracts

Podaci o skupu

Annual meeting of the Croatian Immunological Society 2011

predavanje

07.10.2011-09.10.2011

Rabac, Hrvatska

Povezanost rada

Temeljne medicinske znanosti, Kliničke medicinske znanosti, Biologija