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Human Metabolism Section, Laboratory of Pharmacology and Chemistry (Y.C., S.S.F., J.A.G.), and Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology (M.N.), National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina
CYP2C19 is an important human drug-metabolizing enzyme that metabolizes a
number of clinically used drugs including the antiulcer drug omeprazole, the
anxiolytic drug diazepam, the 
-blocker propranolol, the antimalarial
drug proguanil, certain antidepressants and barbiturates, and the prototype
substrate S-mephenytoin. Previous studies show that compounds such as
rifampicin and dexamethasone induce CYP2C19 both in vivo in humans and in
vitro in human hepatocytes. This study examines the transcriptional regulation
of CYP2C19. Analysis of the CYP2C19 promoter revealed a
single constitutive androstane receptor (CAR) binding site (CAR-RE;
-1891/-1876 bp) and a glucocorticoid-responsive element (GRE; -1750/-1736 bp).
Gel-shift assays showed that CAR-RE binds CAR and pregnane X receptor (PXR).
Cotransfection with hCAR, mCAR, or hPXR in HepG2 cells up-regulated
transcription of CYP2C19 promoter constructs, whereas mutation of the
-1891-bp CAR-RE abolished up-regulation. Expression with hCAR also
up-regulated endogenous CYP2C19 mRNA content in HepG2 cells. Androstenol
repressed the mCAR-mediated constitutive activation of the CYP2C19
promoter in HepG2 cells, whereas the potent mCAR ligand
1,4-bis[2–3,5-dichloropyridyloxyl)] benzene derepressed this
response. Rifampicin produced a modest increase in promoter activity in cells
cotransfected with hPXR. Dexamethasone activated the -2.7-kb CYP2C19
promoter constructs in HepG2 cells only in the presence of cotransfected
glucocorticoid receptor (GR), whereas the GR antagonist mifepristone inhibits
this response. Mutation of the GRE abolishes dexamethasone activation. This is
the first study to identify nuclear receptor binding sites (CAR/PXR and GR) in
the CYP2C19 promoter and to suggest that these receptors may
up-regulate CYP2C19 constitutively and possibly its response to
drugs.
Address correspondence to: Dr. Joyce Goldstein, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. E-mail: goldste1{at}niehs.nih.gov
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