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Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels

(2007) INFLAMMATORY BOWEL DISEASES. 13(6). p.710-720
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Organization
Abstract
Background: Altered P-glycoprotein expression (P-gp/MDR1) and/or function may contribute to the pathogenesis of gastrointestinal inflammatory disorders. Low intestinal mRNA levels of the pregnane X receptor (PXR) have been linked to low MDR1 mRNA levels in patients with ulcerative colitis (UC). Here we compared intestinal MDR1 mRNA and protein expression in uninflamed and inflamed intestinal epithelium (IE) of patients with gastrointestinal inflammatory disorders to healthy controls. Methods: Intestinal mucosal biopsies were obtained from patients with Crohn's disease (CD, n = 20), UC (n = 10), diverticulitis (n = 3), collagenous colitis (n = 3), and healthy controls (n 10). MDR1, iNOS, MRP1, CYP3A4, and PXR expression was determined using real-time reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting, and/or immunohistochemistry. Furthermore, MDR1 expression was determined in human intestinal biopsies and the human colon carcinoma cell line DLD-1 after exposure to cytokines (TNF-alpha, IFN-gamma, and/or IL-1 beta). Results: MDR1 mRNA levels in uninflamed colon of UC patients were comparable to healthy controls, while they were slightly decreased in ileum and slightly increased in colon of CD patients. MDR1 expression, however, was strongly decreased in inflamed IF of CD, UC, collagenous colitis, and diverticulitis patients. A cytokine-dependent decrease of MDR1 expression was observed in human intestinal biopsies, but not in DLD-1 cells. Remarkably, PXR protein levels were equal in uninflamed and inflamed tissue of CD and UC patients despite low PXR mRNA levels in inflamed tissue. Conclusions: MDR1 expression is strongly decreased in inflamed IE of patients with gastrointestinal disorders and this is independent of PXR protein levels. Low MDR1 levels may aggravate intestinal inflammation.
Keywords
LYMPH-NODES, NUCLEAR RECEPTOR, C3435T, RAT-LIVER, SPONTANEOUS-COLITIS, ULCERATIVE-COLITIS, PREGNANE-X-RECEPTOR, MDR1 GENE POLYMORPHISM, MULTIDRUG-RESISTANCE GENE, inflammation, pregnane X receptor, INFLAMMATORY-BOWEL-DISEASE, P-glycoprotein/multidrug resistance 1, intestinal epithelium

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Chicago
Blokzijl, Hans, Sara Vander Borght, Lisette IH Bok, Louis Libbrecht, Mariska Geuken, Fiona AJ Van den Heuvel, Gerard Dijkstra, et al. 2007. “Decreased P-glycoprotein (P-gp/MDR1) Expression in Inflamed Human Intestinal Epithelium Is Independent of PXR Protein Levels.” Inflammatory Bowel Diseases 13 (6): 710–720.
APA
Blokzijl, Hans, Vander Borght, S., Bok, L. I., Libbrecht, L., Geuken, M., Van den Heuvel, F. A., Dijkstra, G., et al. (2007). Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels. INFLAMMATORY BOWEL DISEASES, 13(6), 710–720.
Vancouver
1.
Blokzijl H, Vander Borght S, Bok LI, Libbrecht L, Geuken M, Van den Heuvel FA, et al. Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels. INFLAMMATORY BOWEL DISEASES. 2007;13(6):710–20.
MLA
Blokzijl, Hans, Sara Vander Borght, Lisette IH Bok, et al. “Decreased P-glycoprotein (P-gp/MDR1) Expression in Inflamed Human Intestinal Epithelium Is Independent of PXR Protein Levels.” INFLAMMATORY BOWEL DISEASES 13.6 (2007): 710–720. Print.
@article{3183604,
  abstract     = {Background: Altered P-glycoprotein expression (P-gp/MDR1) and/or function may contribute to the pathogenesis of gastrointestinal inflammatory disorders. Low intestinal mRNA levels of the pregnane X receptor (PXR) have been linked to low MDR1 mRNA levels in patients with ulcerative colitis (UC). Here we compared intestinal MDR1 mRNA and protein expression in uninflamed and inflamed intestinal epithelium (IE) of patients with gastrointestinal inflammatory disorders to healthy controls. 
Methods: Intestinal mucosal biopsies were obtained from patients with Crohn's disease (CD, n = 20), UC (n = 10), diverticulitis (n = 3), collagenous colitis (n = 3), and healthy controls (n 10). MDR1, iNOS, MRP1, CYP3A4, and PXR expression was determined using real-time reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting, and/or immunohistochemistry. Furthermore, MDR1 expression was determined in human intestinal biopsies and the human colon carcinoma cell line DLD-1 after exposure to cytokines (TNF-alpha, IFN-gamma, and/or IL-1 beta). 
Results: MDR1 mRNA levels in uninflamed colon of UC patients were comparable to healthy controls, while they were slightly decreased in ileum and slightly increased in colon of CD patients. MDR1 expression, however, was strongly decreased in inflamed IF of CD, UC, collagenous colitis, and diverticulitis patients. A cytokine-dependent decrease of MDR1 expression was observed in human intestinal biopsies, but not in DLD-1 cells. Remarkably, PXR protein levels were equal in uninflamed and inflamed tissue of CD and UC patients despite low PXR mRNA levels in inflamed tissue. 
Conclusions: MDR1 expression is strongly decreased in inflamed IE of patients with gastrointestinal disorders and this is independent of PXR protein levels. Low MDR1 levels may aggravate intestinal inflammation.},
  author       = {Blokzijl, Hans and Vander Borght, Sara and Bok, Lisette IH and Libbrecht, Louis and Geuken, Mariska and Van den Heuvel, Fiona AJ and Dijkstra, Gerard and Roskams, Tonia AD and Moshage, Han and Jansen, Peter LM and Faber, Klaas Nico},
  issn         = {1078-0998},
  journal      = {INFLAMMATORY BOWEL DISEASES},
  language     = {eng},
  number       = {6},
  pages        = {710--720},
  title        = {Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels},
  url          = {http://dx.doi.org/10.1002/ibd.20088},
  volume       = {13},
  year         = {2007},
}

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