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-Hydroxylase Gene (CYP7A1) Transcription
1 Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA
* To whom correspondence should be addressed. E-mail: jchiang{at}neoucom.edu.
Bile acids, steroids and drugs activate steroid and xenobiotic receptor, PXR (NR1I2),
which induces CYP3A4 in drug metabolism, but inhibits CYP7A1 in bile acid synthesis
in the liver. Rifampicin, a human PXR agonist, inhibits bile acid synthesis and has been
used to treat cholestatic diseases. The objective of this study is to elucidate the
mechanism by which PXR inhibits CYP7A1 gene transcription. The mRNA expression
levels of CYP7A1 and several nuclear receptors known to regulate the CYP7A1 gene
were assayed in human primary hepatocytes by quantitative real time PCR (Q-PCR).
Rifampicin reduced CYP7A1 and small heterodimer partner (SHP, NR02B) mRNA
expression suggesting that SHP was not involved in PXR inhibition of CYP7A1.
Rifampicin inhibited CYP7A1 reporter activity and a PXR binding site was localized to
the bile acid response element-I (BARE-I). Mammalian two-hybrid assays revealed that
PXR interacted with HNF4
(NR2A1) and rifampicin was required. Co-immunoprecipitation
assay confirmed PXR interaction with HNF4. PXR also interacted
with peroxisome proliferator-activated receptor 
co-activator (PGC-1), which
interacted with HNF4 and induced CYP7A1 gene transcription. Rifampicin enhanced
PXR interaction with HNF4 and reduced PGC-1 interaction with HNF4. Chromatin
immunoprecipitation (ChIP) assay showed that PXR, HNF4, and PGC-1 bound to
CYP7A1 chromatin, and rifampicin dissociated PGC-1 from chromatin. These results
suggest that activation of PXR by rifampicin promotes PXR interaction with HNF4 and
blocks PGC-1 activation of HNF4 and results in inhibition of CYP7A1 gene
transcription. Rifampicin inhibition of bile acid synthesis may be a protective
mechanism against drug and bile acid-induced cholestasis.
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