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Molecular Pharmacology

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Research ArticleArticle

CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

Ngome L. Makia and Joyce A. Goldstein
Molecular Pharmacology January 2016, 89 (1) 154-164; DOI: https://doi.org/10.1124/mol.115.100255
Ngome L. Makia
Human Metabolism Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
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Joyce A. Goldstein
Human Metabolism Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
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Abstract

Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor α (PPARα), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARα in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARα response element located at position −2109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARα to this PPARα response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARα, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators.

Footnotes

    • Received June 5, 2015.
    • Accepted October 13, 2015.
  • This work was supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences [Grant Z01 ES021024-32].

  • dx.doi.org/10.1124/mol.115.100255.

  • ↵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: 89 (1)
Molecular Pharmacology
Vol. 89, Issue 1
1 Jan 2016
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Research ArticleArticle

CYP2C8 Is a Novel Target of PPARα in Human Liver

Ngome L. Makia and Joyce A. Goldstein
Molecular Pharmacology January 1, 2016, 89 (1) 154-164; DOI: https://doi.org/10.1124/mol.115.100255

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Research ArticleArticle

CYP2C8 Is a Novel Target of PPARα in Human Liver

Ngome L. Makia and Joyce A. Goldstein
Molecular Pharmacology January 1, 2016, 89 (1) 154-164; DOI: https://doi.org/10.1124/mol.115.100255
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