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Dysregulation of mucosal membrane transporters and drug metabolizing enzymes in ulcerative colitis.
Journal of Pharmaceutical Sciences 2018 September 27
Intestinal transporters and metabolizing enzymes are important factors of the intestinal absorption barrier. Because there is evidence that their expression and function may be affected during inflammatory conditions, we investigated gene expression, protein abundance and regulation of relevant intestinal transporters and metabolizing enzymes in the intestinal mucosa of ulcerative colitis (UC) patients. Specimens from inflamed and non-inflamed tissues of 10 UC patients as well as colonic control tissues of 10 patients without inflammation were subjected to gene (9 enzymes, 15 transporters, 9 cytokines) and microRNA (N=54) expression analysis. Protein abundance was quantified by LC-MS/MS-based targeted proteomics. Gene expression of several metabolizing enzymes (e.g. CYP2C9, UGT1A1) and transporters as ABCB1 (ABCB1), ABCG2 (ABCG2) and monocarboxylate transporter 1 (MCT1, SLC16A1) were significantly decreased during inflammation and negatively correlated to microRNAs. Contrary, multidrug resistance-protein 4 (MRP4, ABCC4), organic anion transporting-polypeptide 2B1 (OATP2B1, SLCO2B1) and organic cation transporter-like 2 (ORCTL2, SLC22A18) were significantly elevated in inflamed tissue. However, on protein level these findings could only be confirmed for MCT1. UC is associated with complex changes in the intestinal expression of enzymes, transporters, cytokines and microRNAs, which may affect efficacy of anti-inflammatory drug therapy or the disease state itself.
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