OBJECTIVE: The nuclear receptor NR1I2 (also called PXR or SXR) is primarily expressed in mouse and human liver and intestines. Direct activation of NR1I2 occurs in response to a range of xenobiotics, which causes the formation of a heterodimer with the RXR receptor. This heterodimer binds to the nuclear receptor response elements of downstream genes such as ABCB1, CYP2C, and CYP3A. This study determined the extent of NR1I2 variation in three world populations. METHODS: Variation in NR1I2 was identified by pooled resequencing in African, Asian, and European populations. Validation was performed in European and African populations using PCR and Pyrosequencing technology. RNA expression of NR1I2, ABCB1 and CYP3A4 was assessed using real-time PCR. RESULTS: Of 36 single nucleotide polymorphisms (SNPs) identified, 24 were in the untranslated region, 8 were intronic, and 4 exonic. Thirty-six percent were unique to the African population. In comparison with previously published data, we identified 13 novel polymorphisms. The NR1I2 -566A > C polymorphism was significantly associated with ABCB1 and CYP3A4 RNA expression in colon tumor (P = 0.04 in both cases), however, this polymorphism was not associated with NR1I2 expression. CONCLUSION: With NR1I2 playing such a large role in the regulation of genes involved in drug metabolism and transport, genetic variation contributing to altered NR1I2 function may have an important clinical impact.
OBJECTIVE: The nuclear receptor NR1I2 (also called PXR or SXR) is primarily expressed in mouse and human liver and intestines. Direct activation of NR1I2 occurs in response to a range of xenobiotics, which causes the formation of a heterodimer with the RXR receptor. This heterodimer binds to the nuclear receptor response elements of downstream genes such as ABCB1, CYP2C, and CYP3A. This study determined the extent of NR1I2 variation in three world populations. METHODS: Variation in NR1I2 was identified by pooled resequencing in African, Asian, and European populations. Validation was performed in European and African populations using PCR and Pyrosequencing technology. RNA expression of NR1I2, ABCB1 and CYP3A4 was assessed using real-time PCR. RESULTS: Of 36 single nucleotide polymorphisms (SNPs) identified, 24 were in the untranslated region, 8 were intronic, and 4 exonic. Thirty-six percent were unique to the African population. In comparison with previously published data, we identified 13 novel polymorphisms. The NR1I2 -566A > C polymorphism was significantly associated with ABCB1 and CYP3A4 RNA expression in colon tumor (P = 0.04 in both cases), however, this polymorphism was not associated with NR1I2 expression. CONCLUSION: With NR1I2 playing such a large role in the regulation of genes involved in drug metabolism and transport, genetic variation contributing to altered NR1I2 function may have an important clinical impact.
Authors: Robert R Freimuth; Ming Xiao; Sharon Marsh; Matthew Minton; Nicholas Addleman; Derek J Van Booven; Howard L McLeod; Pui-Yan Kwok Journal: Hum Mol Genet Date: 2005-10-20 Impact factor: 6.150
Authors: S A Jones; L B Moore; J L Shenk; G B Wisely; G A Hamilton; D D McKee; N C Tomkinson; E L LeCluyse; M H Lambert; T M Willson; S A Kliewer; J T Moore Journal: Mol Endocrinol Date: 2000-01
Authors: E Hustert; A Zibat; E Presecan-Siedel; R Eiselt; R Mueller; C Fuss; I Brehm; U Brinkmann; M Eichelbaum; L Wojnowski; O Burk Journal: Drug Metab Dispos Date: 2001-11 Impact factor: 3.922
Authors: G Bertilsson; J Heidrich; K Svensson; M Asman; L Jendeberg; M Sydow-Bäckman; R Ohlsson; H Postlind; P Blomquist; A Berkenstam Journal: Proc Natl Acad Sci U S A Date: 1998-10-13 Impact factor: 11.205
Authors: Tasmin Reuter; Rolf Warta; Dirk Theile; Andreas D Meid; Juan Pablo Rigalli; Carolin Mogler; Esther Herpel; Niels Grabe; Bernd Lahrmann; Peter K Plinkert; Christel Herold-Mende; Gerhard Dyckhoff; Walter Emil Haefeli; Johanna Weiss Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2015-07-04 Impact factor: 3.000
Authors: Rita Piedade; Elke Schaeffeler; Stefan Winter; Sara Asimus; Matthias Schwab; Michael Ashton; Oliver Burk; José P Gil Journal: Antimicrob Agents Chemother Date: 2012-01-17 Impact factor: 5.191