10.1124/dmd.115.068742; PMCID: PMC4931888
Copyright © 2016 The Author(s). 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.
Drug Metabolism and Disposition
Shakhnovich, V., Vyhlidal, C. A., Friesen, C. A., Hildreth, A., Singh, V., Daniel, J., Kearns, G. L., Leeder, J. Decreased pregnane X receptor expression in children with active crohn's disease Drug Metabolism and Disposition 44, 1066-1069 (2016).