title: Transcriptional Regulation of CYP2D6 Expression.
abstract: CYP2D6-mediated drug metabolism exhibits large interindividual variability. Although genetic variations in the CYP2D6 gene are well known contributors to the variability, the sources of CYP2D6 variability in individuals of the same genotype remain unexplained. Accumulating data indicate that transcriptional regulation of CYP2D6 may account for part of CYP2D6 variability. Yet, our understanding of factors governing transcriptional regulation of CYP2D6 is limited. Recently, mechanistic studies of increased CYP2D6-mediated drug metabolism in pregnancy revealed two transcription factors, small heterodimer partner (SHP) and Krüppel-like factor 9, as a transcriptional repressor and an activator, respectively, of CYP2D6. Chemicals that increase SHP expression (e.g., retinoids and activators of farnesoid X receptor) were shown to downregulate CYP2D6 expression in the humanized mice as well as in human hepatocytes. This review summarizes the series of studies on the transcriptional regulation of CYP2D6 expression, potentially providing a basis to better understand the large interindividual variability in CYP2D6-mediated drug metabolism.
authors.affiliation: Department of Biopharmaceutical Sciences (X.P., M.N., H.J.), and Department of Pharmacy Practice (H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Xian
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Biopharmaceutical Sciences (X.P., M.N., H.J.), and Department of Pharmacy Practice (H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Miaoran
authors.initials: M
authors.lastname: Ning
authors.affiliation: Department of Biopharmaceutical Sciences (X.P., M.N., H.J.), and Department of Pharmacy Practice (H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois yjeong@uic.edu.
authors.forename: Hyunyoung
authors.initials: H
authors.lastname: Jeong
mesh_terms: D000818:Animals; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis / Q000235:genetics*; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D019389:Cytochrome P-450 CYP2D6