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The constitutive active/androstane receptor (CAR) regulates hepatic drug metabolism by activating genes, such as cytochrome P450, and certain transferases. p38 Mitogen-activated protein kinase (MAPK) is highly activated in human primary hepatocytes but barely in human hepatoma cell lines including HepG2 cells. Liganded-CAR induced CYP2B6 mRNA in human primary hepatocytes far more effectively than in HepG2 cells ectopically expressing CAR. In the present study, we found that activation of p38 MAPK by anisomycin potentiated induction of CYP2B6 mRNA by CAR ligand in HepG2 cells to levels observed in ligand-treated human primary hepatocytes. siRNA knockdown of p38 MAPK abrogated the ability of anisomycin to synergistically induce CYP2B6 mRNA. In addition to CYP2B6, anisomycin cotreatment potentiated an increase in CYP2A7 and CYP2C9 mRNAs but not CYP3A4 or UDP-glucuronosyltransferase 1A1 mRNAs. Thus, activated p38 MAPK is required for liganded-CAR to selectively activate a set of genes that encode drug-metabolizing enzymes. Our present results suggest that CAR-mediated induction of these enzymes cannot be understood by ligand binding alone because the specificity and magnitude of induction are codetermined by a given cell signaling, such as p38 MAPK; both physiologic and pathophysiological states of cell signaling may have a strong impact in hepatic drug-metabolizing capability during treatments.

p38 Mitogen–Activated Protein Kinase Regulates Nuclear Receptor CAR that Activates the CYP2B6 Gene