Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
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Role of Human Hepatocyte Nuclear Factor 4α in the Expression of Drug-Metabolizing Enzymes and Transporters in Human Hepatocytes Assessed by Use of Small Interfering RNA
Yoshiteru KAMIYAMATsutomu MATSUBARAKouichi YOSHINARIKiyoshi NAGATAHidetaka KAMIMURAYasushi YAMAZOE
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2007 Volume 22 Issue 4 Pages 287-298

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Abstract

  Hepatocyte nuclear factor 4α (HNF4α) is an important transcription factor in hepatic gene expression. Here, we have investigated the role of HNF4α in the expression of drug-metabolizing enzymes and transporters in human hepatocytes using an adenovirus expressing human HNF4α-small interfering RNA (hHNF4α-siRNA). The hHNF4α-siRNA effectively reduced the mRNA and nuclear protein levels of hHNF4α in a concentration-dependent manner. The hHNF4α-siRNA also decreased the mRNA levels of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A9, SULT2A1, ABCB1, ABCB11, ABCC2, OATP1B1 and OCT1, as well as those of PXR and CAR. To discern the role of these nuclear receptors, we co-infected hepatocytes with hHNF4α-siRNA and PXR- or CAR-expressing adenovirus. The hHNF4α-siRNA-induced reductions of the enzyme and transporter mRNA levels were not restored except CYP2B6 mRNA levels, which were returned to the control level by overexpressing CAR. Furthermore, although hHNF4α-siRNA did not significantly affect the fold-induction of CYP2B6, CYP2C8, CYP2C9, or CYP3A4 mRNA levels following treatment with CYP inducers, the levels in hHNF4α-suppressed cells fell significantly compared to the control. These results suggest that HNF4α plays a dominant role in the expression of drug-metabolizing enzymes and transporters in human hepatocytes, and that HNF4α expression levels is a possible determinant for inter-individual variations in the expression of these enzymes and transporters.

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© 2007 by The Japanese Society for the Study of Xenobiotics
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