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Decreased Pregnane X Receptor Expression in Children with Active Crohn's Disease
Valentina Shakhnovich1, Carrie Vyhlidal2, Craig Friesen2
1The Children's Mercy Hospital, Kansas City, Missouri (V.S., C.V., C.F., V.S., J.D., J.S.L.) University of California San Diego, San Diego, California (A.H.); Arkansas Children's Hospital Research Institute, Little Rock, Arkansas (G.L.K.). Laboratory of origin: The Children's Mercy Hospital vshakhnovich@cmh.edu.
Insights
Pregnane X receptor (PXR) and related gene expression decreased in pediatric Crohn's disease inflamed tissue. This suggests inflammation impacts drug metabolism genes, warranting further PXR research in pediatric Crohn's disease.
Area of Science:
- Gastroenterology
- Molecular Biology
- Pharmacology
Background:
- Pregnane X receptor (PXR) expression is reportedly reduced in animal models of inflammatory bowel disease (IBD).
- Crohn's disease (CD) is a type of IBD affecting children, with potential implications for drug metabolism and response.
Purpose of the Study:
- To investigate differential expression of PXR, cytochrome P450 3A4 (CYP3A4), and villin 1 (VIL1) in pediatric Crohn's disease.
- To compare gene expression in inflamed versus non-inflamed intestinal tissue in children with CD.
Main Methods:
- RNA extracted from intestinal biopsies of 18 children with CD and 12 controls.
- Reverse transcription real-time quantitative PCR used to measure relative mRNA expression of PXR, CYP3A4, and VIL1.
- Data normalized to glyceraldehyde 3-phosphate dehydrogenase; paired t tests used for statistical analysis.
Main Results:
- PXR, CYP3A4, and VIL1 expression were significantly decreased in the inflamed terminal ileum of children with CD compared to their non-inflamed duodenum.
- No significant differences in these gene expressions were observed in controls.
- PXR expression correlated positively with VIL1 and CYP3A4 expression in CD patients.
Conclusions:
- Decreased expression of PXR, CYP3A4, and VIL1 is specific to actively inflamed intestinal tissue in pediatric Crohn's disease.
- Inflammation may influence the expression of genes critical for drug disposition and response.
- Further research into PXR's role in the pathogenesis and treatment of pediatric CD is supported.
Abstract:
Expression of the pregnane X receptor (PXR) has been reported to be decreased in animal models of inflammatory bowel disease (IBD). To investigate the differential expression of PXR in children with Crohn's disease, a type of IBD, RNA was extracted from archived intestinal biopsies from 18 children with Crohn's disease (CD) and 12 age- and sex-matched controls (aged 7-17yrs). The aim of this investigation was to compare the relative mRNA expression of PXR, cytochrome p450 3A4 (CYP3A4), and villin 1 (VIL1) (a marker of epithelial cell integrity) in the inflamed terminal ileum (TI) versus noninflamed duodenum of children with CD. Relative expression was determined via reverse transcription real-time quantitative polymerase chain reaction, data normalized to glyceraldehyde 3-phosphate dehydrogenase, and differences in gene expression explored via paired t tests. PXR expression was decreased in the inflamed TI versus noninflamed duodenum (TI = 1.88 ± 0.89 versus duodenum = 2.5 ± 0.67; P < 0.001) in CD, but not controls (TI = 2.11 ± 0.41 versus duodenum = 2.26 ± 0.61; P = 0.52). CYP3A4 expression was decreased in CD (TI = -0.89 ± 3.11 versus duodenum = 1.90 ± 2.29; P < 0.05), but not controls (TI = 2.46 ± 0.51 versus duodenum = 2.60 ± 0.60; P = 0.61), as was VIL1 (CD TI = 3.80 ± 0.94 versus duodenum = 4.61 ± 0.52; P < 0.001; controls TI = 4.30 ± 0.35 versus duodenum = 4.47 ± 0.40; P = 0.29). PXR expression correlated with VIL1 (r = 0.78, P = 0.01) and CYP3A4 (r = 0.52, P = 0.01) expression. In conclusion, PXR, CYP3A4, and VIL1 expression was decreased only in the actively inflamed small intestinal tissue in children with CD. Our findings suggest that inflammation has the potential to influence expression of genes, and potentially intestinal proteins, important to drug disposition and response. The observed differential patterns of gene expression support further investigation of the role of PXR in the pathogenesis and/or treatment of pediatric Crohn's disease.
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