title: Decreased Pregnane X Receptor Expression in Children with Active Crohn's Disease.
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.
authors.affiliation: The 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.
authors.forename: Valentina
authors.initials: V
authors.lastname: Shakhnovich
authors.affiliation: The 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.
authors.forename: Carrie
authors.initials: C
authors.lastname: Vyhlidal
authors.affiliation: The 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.
authors.forename: Craig
authors.initials: C
authors.lastname: Friesen
authors.affiliation: The 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.
authors.forename: Amber
authors.initials: A
authors.lastname: Hildreth
authors.affiliation: The 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.
authors.forename: Vivekanand
authors.initials: V
authors.lastname: Singh
authors.affiliation: The 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.
authors.forename: James
authors.initials: J
authors.lastname: Daniel
authors.affiliation: The 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.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kearns
authors.affiliation: The 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.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
mesh_terms: D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*
chemical_list: D008840:Microfilament Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C569754:VIL1 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human