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1. Drug Metab Pharmacokinet. 2012 Feb 14. [Epub ahead of print]

Lower expression of HNF4α and PGC1α might impair rifampicin-mediated CYP3A4
induction under conditions where PXR overexpressed in human fetal liver cells.

Takezawa T, Matsunaga T, Aikawa K, Nakamura K, Ohmori S.

Department of Pharmacy, Shinshu University Hospital.

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.

PMID: 22333269 [PubMed - as supplied by publisher]