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Updated: Jul 12, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Nrf2 Regulates the Expression of CYP2D6 by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9)

Ferbian Milas Siswanto1,2, Maria Dara Novi Handayani1, Rita Dewi Firmasyah1

  • 1Department of Chemistry and Biochemistry, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia.

Current Drug Metabolism
|November 2, 2023
PubMed
Abstract

Insights

NF-E2-related factor 2 (Nrf2) inhibits Cytochrome P450 2D6 (CYP2D6) expression. This Nrf2-CYP2D6 regulatory mechanism offers potential as a prognostic factor and therapeutic strategy for Parkinson's disease and liver cancer.

Area of Science:

  • Molecular biology
  • Genetics
  • Translational medicine

Background:

  • Cytochrome P450 2D6 (CYP2D6) expression is linked to Parkinson's disease (PD) and cancer.
  • NF-E2-related factor 2 (Nrf2) is a key regulator of drug-metabolizing genes.

Purpose of the Study:

  • Investigate the transcriptional regulation of CYP2D6 by Nrf2.
  • Analyze the role of Nrf2-CYP2D6 interaction in PD and cancer.

Main Methods:

  • Transient expression of Nrf2 in Hep3B cells.
  • Analysis of CYP2D6 promoter activity and Nrf2 DNA binding via luciferase and ChIP assays.
  • Examination of Nrf2 and CYP2D6 expression in GEO and TCGA datasets.

Main Results:

  • Nrf2 down-regulates CYP2D6 mRNA expression in hepatoma cells.
  • Nrf2 binds to the antioxidant responsive element (ARE) near the KLF9-binding site on the CYP2D6 promoter.
  • Nrf2 and CYP2D6 levels are altered in PD datasets, with Nrf2 negatively correlated with CYP2D6.
  • Decreased CYP2D6 correlates with lower survival in liver cancer patients.

Conclusions:

  • Nrf2 plays an inhibitory role in regulating CYP2D6 expression.
  • Nrf2-dependent regulation of CYP2D6 presents a potential prognostic factor and therapeutic strategy for PD and liver cancer.
Keywords:
CYP2D6KLF9Nrf2Parkinson’s diseaseliver cancer.transcriptional regulation

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