Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes.
OBJECTIVE
Phase 1, phase 2, and cellular efflux transporters are critical components in intestinal barrier function against xenobiotics and bacteria. We therefore performed global gene expression profiling in patients with ulcerative colitis (UC) and Crohn's disease as well as control specimens, with a special emphasis on genes involved in detoxification and epithelial membrane integrity.


METHODS
Mucosal biopsy specimens from nonaffected regions of the colon and the terminal ileum were subjected to DNA microarray analysis and pathway-related data mining. Real-time reverse-transcription polymerase chain reaction was used for verification of selected regulated candidate genes in larger inflammatory bowel disease sample numbers and intestinal cell lines.


RESULTS
Several dysregulated genes were identified in both disease groups and tissues. A set of genes coordinately down-regulated in the colon of patients with UC was composed of cellular detoxification and defense genes, which are target genes for the transcription factor pregnane X receptor (PXR). Messenger RNA expression of ABCB1 (MDR1) and PXR was significantly reduced in the colon of patients with UC but was unaffected in patients with Crohn's disease. In contrast to some of its target genes, the expression of PXR was not sensitive to tumor necrosis factor alpha stimulation of intestinal cell lines.


CONCLUSIONS
A disease- and tissue-specific decrease in the expression of detoxification enzymes and ABC transporters was observed, which may be explained by a loss of PXR expression. Thus, dysregulation of xenobiotic metabolism and PXR activity in the gut is likely to contribute to the pathophysiology of UC.
Langmann
Thomas
T
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
Moehle
Christoph
C
Mauerer
Richard
R
Scharl
Michael
M
Liebisch
Gerhard
G
Zahn
Alexandra
A
Stremmel
Wolfgang
W
Schmitz
Gerd
G
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008875:Middle Aged; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors