PT  - JOURNAL ARTICLE
AU  - Gerbal-Chaloin, Sabine
AU  - Pascussi, Jean-Marc
AU  - Pichard-Garcia, Lydiane
AU  - Daujat, Martine
AU  - Waechter, Felix
AU  - Fabre, Jean-Michel
AU  - Carrère, Nicolas
AU  - Maurel, Patrick
TI  - Induction of CYP2C Genes in Human Hepatocytes in Primary Culture
DP  - 2001 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 242--251
VI  - 29
IP  - 3
4099  - http://dmd.aspetjournals.org/content/29/3/242.short
4100  - http://dmd.aspetjournals.org/content/29/3/242.full
SO  - Drug Metab Dispos2001 Mar 01; 29
AB  - The expression and inducibility of four CYP2C genes, including CYP2C8, -2C9, -2C18, and -2C19, was investigated in primary cultures of human hepatocytes. By the use of RNase protection assay and specific antibodies, each CYP2C mRNA and protein were quantified unequivocally. The four CYP2C mRNAs were expressed in human livers and cultured primary hepatocytes, but only the CYP2C18 protein was not detected. Compounds known to activate the pregnane X receptor (PXR) such as rifampicin, or the constitutively activated receptor (CAR) such as phenobarbital, induced CYP2C8, CYP2C9, and to a lesser extent CYP2C19 mRNAs and proteins. CYP2C18 mRNA was expressed but not inducible. The concentration dependence of CYP2C8 and CYP2C9 mRNAs in response to rifampicin and phenobarbital paralleled that of CYP3A4 and CYP2B6, the maximum accumulation being reached with 10 μM rifampicin and 100 μM phenobarbital. In contrast, dexamethasone produced maximum induction of CYP2C8 and CYP2C9 mRNAs at 0.1 μM while in these conditions neither CYP3A4 nor CYP2B6 was significantly induced. Moreover, the concentration dependence of CYP2C8 and CYP2C9 mRNAs in response to dexamethasone paralleled that of tyrosine aminotransferase. Furthermore, dexamethasone, which has been recently shown to up-regulate PXR and CAR expression through the glucocorticoid receptor, potentiated CYP2C8 and CYP2C9 mRNA induction in response to rifampicin and phenobarbital. Collectively, these results suggest the possible implication of at least three receptors in the regulation of CYP2C8 and CYP2C9expression, i.e., glucocorticoid receptor, PXR, and/or CAR. The American Society for Pharmacology and Experimental Therapeutics