Premium
Inducers of Small Heterodimer Partner Expression Lead to Decreased CYP2D6 Expression and Activity
Author(s) -
PAN XIAN,
Jeong Hyunyoung
Publication year - 2015
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.29.1_supplement.778.9
Subject(s) - small heterodimer partner , transactivation , transcription factor , biology , microbiology and biotechnology , nuclear receptor , chemistry , biochemistry , gene
Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6‐mediated drug metabolism. However, factors governing CYP2D6 transcription are largely unknown. We recently demonstrated small heterodimer partner (SHP) as a novel transcriptional regulator of CYP2D6 expression; SHP represses transactivation of CYP2D6 promoter by hepatocyte nuclear factor 4α. The objective of this study is to investigate whether extrinsic modulators of SHP alter CYP2D6 expression and activity. Methods. We examined whether known inducers of SHP expression—GW4064 [an agonist of farnesoid X receptor], all‐trans retinoic acid (atRA), and estrogen—alter CYP2D6 expression and activity in vitro and in vivo . Results. In primary human hepatocytes, treatment of GW4064 (10 μM) or atRA (1 μM) for 48 hours led to a 2‐fold decrease in CYP2D6 expression and a 20% decrease in CYP2D6 activity. In CYP2D6‐humanized transgenic mice, the administration of GW4064 (10 mg/kg, i.p.), atRA (5 mg/kg, i.p.), or ethinylestradiol (10 mg/kg, s.c.) for 5 days decreased CYP2D6 expression and activity by 2 to 3‐fold, accompanied by increased SHP expression (by 2 to 3‐fold) as well as increased recruitment of SHP to CYP2D6 promoter in mouse livers. CYP2D6 repression by GW4064 was abrogated in Shp ‐null mice, indicating a critical role of SHP in the drug action. Conclusion Our results demonstrate that inducers of SHP expression repress hepatic CYP2D6 expression, suggesting that differential levels of SHP modulators may contribute to interindividual variability in CYP2D6‐mediated drug metabolism. This study is supported by NIH (R01HD065532).