title: Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels.
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-1beta).
  
  
  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 IE 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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Blokzijl
authors.forename: Sara
authors.initials: S
authors.lastname: Vander Borght
authors.forename: Lisette I H
authors.initials: LI
authors.lastname: Bok
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Mariska
authors.initials: M
authors.lastname: Geuken
authors.forename: Fiona A J
authors.initials: FA
authors.lastname: van den Heuvel
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
authors.forename: Tania A D
authors.initials: TA
authors.lastname: Roskams
authors.forename: Han
authors.initials: H
authors.lastname: Moshage
authors.forename: Peter L M
authors.initials: PL
authors.lastname: Jansen
authors.forename: Klaas Nico
authors.initials: KN
authors.lastname: Faber
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics*; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015415:Biomarkers; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid