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Research ArticleArticle

Contribution of Hepatocyte Nuclear Factor-4 to Down-Regulation ofCYP2D6 Gene Expression by Nitric Oxide

Hirokazu Hara and Tetsuo Adachi
Molecular Pharmacology January 2002, 61 (1) 194-200; DOI: https://doi.org/10.1124/mol.61.1.194
Hirokazu Hara
Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
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Tetsuo Adachi
Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
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Abstract

Nitric oxide (NO) released under inflammatory and infectious conditions has been implicated in the down-regulation of many cytochrome P450 genes, but its mechanism of action remains unknown. We showed that the expression of the CYP2D6 gene is down-regulated at the transcriptional level by NO in HepG2 cells. The NO donor (±)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-1-yl]-3-pyridine carboxamide (NOR4) decreased the expression of CYP2D6 mRNA in a concentration-dependent manner. Using a CYP2D6 promoter-luciferase construct, we found that NOR4 and another NO donor,S-nitrosoglutathione (GSNO), reduced the luciferase activity in a concentration-dependent manner. A guanylate-cyclase inhibitor failed to prevent suppression of CYP2D6 promoter activity by GSNO, indicating that the activity of the CYP2D6 promoter is suppressed via an NO-guanylate cyclase-independent pathway. Deletion analysis of the CYP2D6 promoter revealed that the −80 to +65 region, which contains the nuclear receptor hepatocyte nuclear factor-4 (HNF4) binding site, was responsible for the suppression of CYP2D6 promoter activity by NO. Therefore, we examined NO responsiveness of the HNF4 binding site by electrophoretic mobility-shift assays and site-direct mutagenesis. The DNA-binding activity of HNF4 was directly inhibited by NO donors, GSNO, andS-nitroso-N-acetyl-penicillamine in a concentration-dependent manner. Mutation of the HNF4 binding site in the CYP2D6 promoter partially restored the suppression of the promoter activity by NO donors. These results demonstrated that NO down-regulates CYP2D6 gene expression, at least in part, by directly inhibiting HNF4 binding to the CYP2D6 promoter.

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Molecular Pharmacology: 61 (1)
Molecular Pharmacology
Vol. 61, Issue 1
1 Jan 2002
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Research ArticleArticle

Contribution of Hepatocyte Nuclear Factor-4 to Down-Regulation ofCYP2D6 Gene Expression by Nitric Oxide

Hirokazu Hara and Tetsuo Adachi
Molecular Pharmacology January 1, 2002, 61 (1) 194-200; DOI: https://doi.org/10.1124/mol.61.1.194

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Research ArticleArticle

Contribution of Hepatocyte Nuclear Factor-4 to Down-Regulation ofCYP2D6 Gene Expression by Nitric Oxide

Hirokazu Hara and Tetsuo Adachi
Molecular Pharmacology January 1, 2002, 61 (1) 194-200; DOI: https://doi.org/10.1124/mol.61.1.194
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