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Fenofibrate upregulates SHP expression but does not alter CYP2D6 expression
Author(s) -
Kent Rebecca,
Jeong Hyunyoung
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.713.4
Subject(s) - fenofibrate , small heterodimer partner , cyp2d6 , downregulation and upregulation , messenger rna , gene expression , cytochrome p450 , chemistry , endocrinology , pharmacology , medicine , biology , transcription factor , metabolism , biochemistry , gene , nuclear receptor
Cytochrome P450 (CYP) 2D6 is a major drug‐metabolizing enzyme, responsible for eliminating 25% of marketed drugs. Factors involved in transcriptional regulation of CYP2D6 are poorly understood, and we recently identified SHP as a negative regulator of CYP2D6 expression (1). Factors that alter SHP expression could influence CYP2D6 expression, and therefore the extent of CYP2D6‐mediated drug metabolism. Fenofibrate has been previously reported to upregulate SHP expression in mouse liver (2). Our objective was to determine whether fenofibrate negativley alters CYP2D6 expression via upregulating SHP expression. CYP2D6‐humanized transgenic mice were administered with fenofibrate (100 mg/kg/day intraperitoneally for 5 days) or vehicle control. Hepatic mRNA and protein expression levels of CYP2D6 and SHP were measured. Results showed that while mRNA levels of SHP did not differ between the groups, protein levels of SHP increased by 2‐fold in fenofibrate‐treated mice. Despite the increased SHP protein levels, CYP2D6 expression did not decrease at the mRNA or protein levels. Similar results were observed in human hepatocytes treated with fenofibrate (at 200 μM for 48 hr). These results indicate that has minimal effects on CYP2D6 expression although it enhances SHP expression. Support or Funding Information This study was supported by NIH (GM112746 and HD065532).