Role of Human Hepatocyte Nuclear Factor 4.ALPHA. in the Expression of Drug-Metabolizing Enzymes and Transporters in Human Hepatocytes Assessed by Use of Small Interfering RNA

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  • KAMIYAMA Yoshiteru
    Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
  • MATSUBARA Tsutomu
    Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University Tohoku University 21st Century, COE Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation”
  • YOSHINARI Kouichi
    Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University
  • NAGATA Kiyoshi
    Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University Department of Environmental Health Science, Tohoku Pharmaceutical University
  • KAMIMURA Hidetaka
    Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc.
  • YAMAZOE Yasushi
    Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University Tohoku University 21st Century, COE Program “Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation”

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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
  • Role of human hepatocyte nuclear factor 4a in the expression of drug-metabolizing enzymes and transporters in human hepatocytes assessed by use of small interfering RNA

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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.<br>

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