RT Journal Article
SR Electronic
T1 HUMAN PXR VARIANTS AND THEIR DIFFERENTIAL EFFECTS ON THE REGULATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE GENE EXPRESSION
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 340
OP 347
DO 10.1124/dmd.32.3.340
VO 32
IS 3
A1 Dione Gardner-Stephen
A1 Jean-Marie Heydel
A1 Amit Goyal
A1 Yuan Lu
A1 Wen Xie
A1 Tim Lindblom
A1 Peter Mackenzie
A1 Anna Radominska-Pandya
YR 2004
UL http://dmd.aspetjournals.org/content/32/3/340.abstract
AB The pregnane X receptor (PXR) has three known major transcript variants resulting from alternative splicing. The less well characterized variants T2 and T3 are identical to the well described variant T1 except for a 39-amino acid N-terminal extension in T2 and an internal 37-amino acid deletion in T3. We have developed reverse transcription-polymerase chain reaction (RT-PCR) methods to detect and quantify each human PXR (hPXR) in human liver and intestinal tissues and HepG2 and Caco-2 cell lines. All three isoforms were expressed in hepatic cells, whereas only T1 transcripts were found in Caco-2 cells. In general, most normal human liver and intestinal mucosa contained all three hPXR variants, but considerable interindividual variation in expression levels was found. The effect of each hPXR variant on expression of UDP-glucuronosyltransferase (UGT) UGT1A and UGT2B family isoforms was investigated in transiently transfected HepG2 and Caco-2 cells. As a family, UGT1A transcripts were up-regulated by T1 and T2 but not T3. Isoform-specific RT-PCR revealed that UGT1A1, 1A3, and 1A4 were the major isoforms induced in both cell lines. The levels of several UGT1A isoforms were also examined in human liver samples from a number of donors with characterized PXR expression. The data suggest that individual variation in PXR expression may account for differential expression of some UGT isoforms between subjects. The American Society for Pharmacology and Experimental Therapeutics