title: Lower expression of HNF4α and PGC1α might impair rifampicin-mediated CYP3A4 induction under conditions where PXR is overexpressed in human fetal liver cells.
abstract: Pregnane X receptor (PXR) mRNA was detected in HepG2 cells by RT-PCR, but not in human fetal liver (HFL) cells. CYP3A4 was induced by rifampicin (RIF), mifepristone (RU486), clotrimazole (CTZ), and dexamethasone (DEX) in HepG2 cells, while these PXR ligands with the exception of DEX did not induce CYP3A4 mRNA expression in HFL cells. Ad-PXR infection increased mRNA levels of PXR and CYP3A4 in both cells despite the absence of PXR ligands. Similar results were observed in reporter gene assays. However, in HFL cells, RIF-mediated CYP3A4 induction was insufficient compared with HepG2 cells, despite PXR overexpression. The expression levels of five coactivators (HNF4α, PGC1α, SRC1, CBP, and P300) related to CYP3A4 expression in HepG2, HFL cells, and human adult liver were analyzed by RT-PCR. Expression levels of HNF4α and PGC1α in HFL cells were downregulated to 20% of those in the human adult liver. On the other hand, the expression level of HNF4α in HepG2 cells was higher than that in HFL cells, although PGC1α expression level was almost the same as that in HFL cells. HNF4α mRNA expression level in HepG2 cells was 57% of that in human adult liver, and the level in HFL cells was 30% of that in HepG2 cells. These results suggested that lower expression of HNF4α and PGC1α may impair RIF-mediated CYP3A4 induction under conditions of PXR overexpression in HFL cells.
authors.affiliation: Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takezawa
authors.forename: Tamihide
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Kaori
authors.initials: K
authors.lastname: Aikawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohmori
mesh_terms: D050882:CREB-Binding Protein / Q000378:metabolism; D003022:Clotrimazole / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation; D004790:Enzyme Induction; D017930:Genes, Reporter; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology; D015735:Mifepristone / Q000494:pharmacology; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C496592:HNF4A protein, human; D006360:Heat-Shock Proteins; D051557:Hepatocyte Nuclear Factor 4; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors; D015735:Mifepristone; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D050880:p300-CBP Transcription Factors; D003022:Clotrimazole; D012293:Rifampin