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Research ArticleArticle

Regulation of Human CYP2C9 Expression by Electrophilic Stress Involves Activator Protein 1 Activation and DNA Looping

Ngome L. Makia, Sailesh Surapureddi, Katalin Monostory, Russell A. Prough and Joyce A. Goldstein
Molecular Pharmacology August 2014, 86 (2) 125-137; DOI: https://doi.org/10.1124/mol.114.092585
Ngome L. Makia
Human Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (N.L.M., S.S., J.A.G.); Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky (R.A.P.); and Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary (K.M.)
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Sailesh Surapureddi
Human Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (N.L.M., S.S., J.A.G.); Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky (R.A.P.); and Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary (K.M.)
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Katalin Monostory
Human Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (N.L.M., S.S., J.A.G.); Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky (R.A.P.); and Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary (K.M.)
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Russell A. Prough
Human Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (N.L.M., S.S., J.A.G.); Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky (R.A.P.); and Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary (K.M.)
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Joyce A. Goldstein
Human Metabolism Group, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina (N.L.M., S.S., J.A.G.); Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky (R.A.P.); and Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary (K.M.)
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Abstract

Cytochrome P450 (CYP)2C9 and CYP2C19 are important human enzymes that metabolize therapeutic drugs, environmental chemicals, and physiologically important endogenous compounds. Initial studies using primary human hepatocytes showed induction of both the CYP2C9 and CYP2C19 genes by tert-butylhydroquinone (tBHQ). As a pro-oxidant, tBHQ regulates the expression of cytoprotective genes by activation of redox-sensing transcription factors, such as the nuclear factor E2-related factor 2 (Nrf2) and members of the activator protein 1 (AP-1) family of proteins. The promoter region of CYP2C9 contains two putative AP-1 sites (TGAGTCA) at positions −2201 and −1930, which are also highly conserved in CYP2C19. The CYP2C9 promoter is activated by ectopic expression of cFos and JunD, whereas Nrf2 had no effect. Using specific kinase inhibitors for mitogen-activated protein kinase, we showed that extracellular signal-regulated kinase and Jun N-terminal kinase are essential for tBHQ-induced expression of CYP2C9. Electrophoretic mobility shift assays demonstrate that cFos distinctly interacts with the distal AP-1 site and JunD with the proximal site. Because cFos regulates target genes as heterodimers with Jun proteins, we hypothesized that DNA looping might be required to bring the distal and proximal AP-1 sites together to activate the CYP2C9 promoter. Chromosome conformation capture analyses confirmed the formation of a DNA loop in the CYP2C9 promoter, possibly allowing interaction between cFos at the distal site and JunD at the proximal site to activate CYP2C9 transcription in response to electrophiles. These results indicate that oxidative stress generated by exposure to electrophilic xenobiotics and metabolites induces the expression of CYP2C9 and CYP2C19 in human hepatocytes.

Footnotes

    • Received March 7, 2014.
    • Accepted May 14, 2014.
  • This work was supported in part by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences [Project ES021024]; National Institutes of Health National Institute of Environmental Health Sciences [Grant ES11860]; National Development Agency [GOP-1.3.1-11/B-2011-0042]; and Hungarian Scientific Research Fund [OTKA K104459].

  • dx.doi.org/10.1124/mol.114.092585.

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

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 86 (2)
Molecular Pharmacology
Vol. 86, Issue 2
1 Aug 2014
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Research ArticleArticle

Regulation of CYP2C9 by AP-1 Activation and DNA Looping

Ngome L. Makia, Sailesh Surapureddi, Katalin Monostory, Russell A. Prough and Joyce A. Goldstein
Molecular Pharmacology August 1, 2014, 86 (2) 125-137; DOI: https://doi.org/10.1124/mol.114.092585

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Research ArticleArticle

Regulation of CYP2C9 by AP-1 Activation and DNA Looping

Ngome L. Makia, Sailesh Surapureddi, Katalin Monostory, Russell A. Prough and Joyce A. Goldstein
Molecular Pharmacology August 1, 2014, 86 (2) 125-137; DOI: https://doi.org/10.1124/mol.114.092585
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