The Pregnane X Receptor Locus Is Associated With Susceptibility to Inflammatory Bowel Disease

Dring, Megan; Goulding, Carol; Trimble, Valerie; Keegan, Denise; Ryan, Anthony W.; Brophy, K.; Smyth, C; Keeling, P. W. N.; O’Donoghue, Diarmuid; O’Sullivan, Maria; O’Moráin, Colm; Mahmud, Nasir; Wikström, Ann–Charlotte; Kelleher, Dermot; McManus, Ross

doi:10.1053/j.gastro.2005.12.008

Cited by 148 publications

(135 citation statements)

References 27 publications

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“…Upon ectopic expression of PXR through transfection, the PXR function could be restored and cells showed significant reduced proliferation, suggesting its role in controlling tumour cell proliferation. It has been reported that certain polymorphisms of PXR were identified to be strongly associated with the susceptibility to IBD (Dring et al, 2006), which is a significant risk factor for colon cancer. In patients with IBD, decreased expressions of PXR and its target genes have been observed (Langmann et al, 2004;Martinez et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Ouyang

Eagleton

et al. 2010

Br J Cancer

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BACKGROUND: Pregnane X receptor (PXR) is a nuclear receptor that regulates the metabolism and disposition of various xenobiotics and endobioitics. We investigated a novel PXR function in regulating colon tumourigenesis in this study. METHODS: Histochemistry, transfection, cell proliferation assay, anchorage-a-dependent assay, xenograft, immunohistochemistry, immunofluorescence flow cytometry. RESULTS: Using histochemistry analysis, we found that PXR expressions were lost or greatly diminished in many colon tumours. Ectopic expression of human PXR through stable transfection of PXR into colon cancer cell line HT29 significantly inhibited cell proliferation as determined by cell proliferation assay and anchorage-independent assay. Pregnane X receptor suppressed significantly HT29 xenograft tumour growth in nude mice compared with control (310±6.2 vs 120±6 mg, Po0.01). Immunohistochemistry and immunofluorescence analysis of Ki-67 on excised xenograft tumour tissues showed that PXR inhibited cancer cell proliferation. Furthermore, expressions of PXR and Ki-67 were mutually exclusive. The flow cytometry analysis indicated that PXR caused G 0 /G 1 cell-cycle arrest. p21 WAF1/CIP1 expression was markedly elevated whereas E2F1 expression was inhibited by PXR. CONCLUSION: PXR inhibits the proliferation and tumourigenicity of colon cancer cells by controlling cell cycle at G 0 /G 1 cell phase by regulating p21 WAF1/CIP1 and E2F/Rb pathways.

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Section: Discussionmentioning

confidence: 99%

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Ouyang

Eagleton

et al. 2010

Br J Cancer

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“…The Tagger pairwise function within HapMap assigned 13 tag SNPs (rs2056530, rs10934498, rs1357459, rs2461822, rs2461818, rs7643645, rs2472681, rs11917714, rs6785049, rs11929668, rs3732359, rs3732360, and rs1054190) to capture .80% of the common variation within this gene and surrounding area. In addition, previously investigated SNPs A7635G (rs6785049) 37 and C8055T (rs2276707), 37 which were represented by the tag SNP 225385C.T (rs3814055), 38 were also assessed.…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

Moore

McKnight

Döhler

et al. 2012

Journal of the American Society of Nephrology

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The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential influence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 (MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.20-2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08-3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation.

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“…Susceptibilty to inflammatory bowel disease has been shown to be associated with genetic variation in the PXR encoding gene. 12 In a study of the PXR gene, Karlsen et al 13 did not find that susceptibility to PSC was associated with any of the polymorphisms which they chose to study but found that certain genotypes exerted a significant effect on diminished survival in PSC patients. The impaired functioning of PXR coordinated biotransformation and transport mechanisms shared by liver and intestine could also be anticipated to impact upon the susceptibility to recurrent PSC in the transplanted liver which pertains in those whose colon is intact but not in those who have undergone total colectomy (Fig 5).…”

Section: Defective Mechanisms and Disease Susceptibilitymentioning

confidence: 99%

Coordinated defence and the liver

Elias

Mills

2007

Clinical Medicine

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-The liver is strategically placed to protect the body against a vast array of potentially harmful compounds. The steps involved include phase I metabolism which makes molecules more reactive and phase II reactions which generally enhance solubility in bile or urine. Recent discoveries have shown how regulation of these reactions is also closely allied to expression of membrane transporters which excrete the products of biotransformation into bile and prevent their reabsorptoion via the intestine. The coordinated activity of these various functions is orchestrated by orphan nuclear receptors which, in response to an encounter with a potential toxin, are able to induce expression of the genes involved in its biotransformation and excretion. Lithocholic acid (LCA) is routinely produced in our intestine by bacterial deconjugation of chenodeoxycholic acid a major bile acid in humans. In human liver the presence of LCA is sensed by the pregnane X receptor (PXR) which has the potential to switch on all the genes required for safe metabolism and elimination of LCA from the body. These include cytochrome P450 3A which hydroxylates LCA to more soluble forms and sulfotransferase (SULT2A1) which by sulphation of LCA makes it more readily soluble in bile and enhances its faecal excretion. Similarly, PXR exposure to LCA produces up-regulated expression of the membrane transporters MDR1 and MRP2 which excrete metabolites of LCA. Evidence is accumulating in support of the hypothesis that deficiencies in these defence mechanisms underlie susceptibility to primary sclerosing cholangitis and ulcerative colitis. KEY WORDS: cytochrome P450 3A, lithocholic acid, MDR1 and MRP2, orphan nuclear receptors, pregnane X receptor, sulphation, susceptibility to primary sclerosing cholangitis, ulcerative colitisThe liver metabolises and excretes a host of endogenous molecules and stands at the portal of entry for all kinds of ingested xenobiotics, whether food or drug. The fate of these compounds depends largely on the efficiency of their absorption from the gut and uptake and biotransformation by the liver. The mechanisms involved include metabolic transformation and active transport which usually work in combination to enhance elimination from the body whether in urine or faeces. In this the liver is closely allied with the intestine in maintaining the functionality of bile as a safe route for elimination of any potentially toxic compound that lacks sufficient solubility in water to permit its efficient excretion via the kidneys. The detergent properties of bile facilitate efficient excretion of compounds which are poorly soluble in water. Coordinated biliary defence mechanismsBile acids provide the required detergency and are essential for biliary cholesterol secretion and absorption of fat and fat soluble vitamins. The synthesis of bile acids by the liver is closely regulated to compensate for faecal loss, thus maintaining a consistent pool of bile acids in the entero-hepatic circulation which re-circulate from liver to intestine...

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The Pregnane X Receptor Locus Is Associated With Susceptibility to Inflammatory Bowel Disease

Cited by 148 publications

References 27 publications

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

Coordinated defence and the liver

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