Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes.

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Sahi J, Shord SS, Lindley C, Ferguson S, LeCluyse EL

Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes.

J Biochem Mol Toxicol. 2009 Jan-Feb;23(1):43-58. doi: 10.1002/jbt.20264.

PubMed ID

19202563 [ View in PubMed

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Abstract

Cytochrome P450 2C9 (CYP2C9) expression is regulated by multiple nuclear receptors including the constitutive androstane receptor (CAR) and pregnane X receptor (PXR). We compared coregulation of CYP2C9 with CYP2B6 and CYP3A4, prototypical target genes for human CAR and PXR using human hepatocyte cultures treated for three days with the PXR activators clotrimazole, rifampin, and ritonavir; the CAR/PXR activator phenobarbital (PB); and the CAR-selective agonists CITCO, (6-(4-chlorophenyl)imidazo[2,1-beta][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorob enzyl)oxime) and phenytoin. Clotrimazole, rifampin, ritonavir, phenytoin, and phenobarbital induced CYP2C9 consistent with previous findings for CYP3A4. We observed EC(50) values of 519 microM (phenobarbital), 11 microM (phenytoin), and 0.75 microM (rifampin), similar to those for CYP3A4 induction. Avasimibe, a potent PXR activator, produced nearly identical concentration-dependent CYP2C9 and CYP3A4 activity profiles and EC(50) values. In 17 donors, rifampin increased mean basal CYP2C9 activity from 59 +/- 43 to 143 +/- 68 pmol/mg protein/min; fold induction ranged from 1.4- to 6.4-fold. Enzyme activity and mRNA measurements after rifampin, CITCO and PB treatment demonstrated potency and efficacy consistent with CYP2C9 regulation being analogous to CYP3A4 rather than CYP2B6. We demonstrate that hepatic CYP2C9 is differentially regulated by agonists of CAR and PXR, and despite sharing common regulatory mechanisms with CYP3A4 and CYP2B6; this enzyme exhibits an induction profile more closely aligned with that of CYP3A4.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Fosphenytoin	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Rifampicin	Approved	CYP2B6	1555	upregulated	Rifampin results in increased expression of CYP2B6 mRNA	19q13.2
Rifampicin	Approved	CYP2C9	1559	upregulated	Rifampin results in increased expression of CYP2C9 mRNA	10q23.33
Rifampicin	Approved	CYP3A4	1576	upregulated	Rifampin results in increased expression of CYP3A4 mRNA	7q22.1