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Research ArticleArticle

Downregulation of CYP1A2, CYP2B6, and CYP3A4 in Human Hepatocytes by Prolyl Hydroxylase Domain 2 Inhibitors via Hypoxia-Inducible Factor-α Stabilization

Hiroki Takano, Jun-ichi Yamaguchi, Sota Kato, Makoto Hamada, Mika Tada and Hiromi Endo
Drug Metabolism and Disposition January 2021, 49 (1) 20-30; DOI: https://doi.org/10.1124/dmd.120.000124
Hiroki Takano
Drug Safety and Pharmacokinetics Laboratories (H.T., J.Y., M.T., H.E.), Pharmacology Laboratories (S.K.), and Chemistry Laboratories (M.H.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Jun-ichi Yamaguchi
Drug Safety and Pharmacokinetics Laboratories (H.T., J.Y., M.T., H.E.), Pharmacology Laboratories (S.K.), and Chemistry Laboratories (M.H.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Sota Kato
Drug Safety and Pharmacokinetics Laboratories (H.T., J.Y., M.T., H.E.), Pharmacology Laboratories (S.K.), and Chemistry Laboratories (M.H.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Makoto Hamada
Drug Safety and Pharmacokinetics Laboratories (H.T., J.Y., M.T., H.E.), Pharmacology Laboratories (S.K.), and Chemistry Laboratories (M.H.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Mika Tada
Drug Safety and Pharmacokinetics Laboratories (H.T., J.Y., M.T., H.E.), Pharmacology Laboratories (S.K.), and Chemistry Laboratories (M.H.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Hiromi Endo
Drug Safety and Pharmacokinetics Laboratories (H.T., J.Y., M.T., H.E.), Pharmacology Laboratories (S.K.), and Chemistry Laboratories (M.H.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan
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Abstract

Hypoxia-inducible factor (HIF) is associated with the expression of CYP, but the underlying mechanism remains uncertain. In this study, we investigated the effect of HIF-α stabilization caused by novel prolyl hydroxylase domain (PHD) 2 inhibitors, which are HIF-α stabilizers that mimic hypoxia, on the expressions of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. An mRNA expression analysis of human hepatocytes treated with PHD2 inhibitors for 72 hours showed the downregulation of genes encoding CYP1A2, CYP2B6, and CYP3A4. The mRNA repressions were accompanied with an increase in erythropoietin protein, a marker of HIF-α stabilization, indicating that HIF-α stabilization was involved in the downregulation of the CYP isoforms. To understand the underlying mechanisms, we assessed the relationship between the expressions of the CYP isoforms and those of their regulating transcription factors [aryl hydrocarbon receptor (AhR), AhR nuclear translocator (ARNT), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoid X receptor (RXR)] in human hepatocytes treated with the HIF-α stabilizers. As a result, the mRNA level of AhR did not decrease, although ARNT expression was repressed. On the other hand, the mRNA expression levels of CAR, PXR, and RXR were repressed and closely associated with those of CYP2B6 and CYP3A4. Although the underlying mechanism of the downregulation for CYP1A2 remains unclear, the presently reported results suggest that the downregulation of CYP2B6 and CYP3A4 via HIF-α stabilization is caused by a decrease in the expressions of CAR, PXR, and RXR.

SIGNIFICANCE STATEMENT We showed that hypoxia-inducible factor (HIF)-α stabilization downregulates CYP1A2, CYP2B6, and CYP3A4 using prolyl hydroxylase domain 2 inhibitors, which are HIF-α stabilizers, as a new tool to mimic hypoxia in human hepatocytes. To understand the underlying mechanisms, we assessed the relationship between the expressions of the CYP isoforms and those of their regulating transcription factors. Our findings would contribute to a better understanding of the hypoxia-triggered regulatory mechanism of drug-metabolizing enzymes in human hepatocytes.

Footnotes

    • Received May 19, 2020.
    • Accepted October 2, 2020.
  • The authors in this work are all employees of Taisho Pharmaceutical Co., Ltd. The authors received no outside funding for this work.

  • https://doi.org/10.1124/dmd.120.000124.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
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Research ArticleArticle

Downregulation of CYP Enzymes by PHD2 Inhibitors

Hiroki Takano, Jun-ichi Yamaguchi, Sota Kato, Makoto Hamada, Mika Tada and Hiromi Endo
Drug Metabolism and Disposition January 1, 2021, 49 (1) 20-30; DOI: https://doi.org/10.1124/dmd.120.000124

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Research ArticleArticle

Downregulation of CYP Enzymes by PHD2 Inhibitors

Hiroki Takano, Jun-ichi Yamaguchi, Sota Kato, Makoto Hamada, Mika Tada and Hiromi Endo
Drug Metabolism and Disposition January 1, 2021, 49 (1) 20-30; DOI: https://doi.org/10.1124/dmd.120.000124
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