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p38 MAPK signaling determines CAR‐mediated activation of the CYP2B genes by xenobiotics
Author(s) -
Saito Kosuke,
Moore Rick,
Negishi Masahiko
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.673.3
Subject(s) - pregnane x receptor , cyp2b6 , mapk/erk pathway , constitutive androstane receptor , microbiology and biotechnology , p38 mitogen activated protein kinases , gene knockdown , activator (genetics) , anisomycin , signal transduction , biology , chemistry , cyp3a4 , cytochrome p450 , receptor , nuclear receptor , gene , biochemistry , transcription factor , kinase , enzyme
The current concept for how liver eliminates xenobiotics and therapeutics is: these chemicals activate nuclear receptors CAR and/or PXR which in turn activate genes that encode for enzymes and transporters that metabolize and excrete them, such as the cytochrome P450s (CYPs). Here, we have demonstrated that p38 MAPK signaling is required for CAR to effectively and selectively activate a set of CYP genes and have investigated its molecular mechanism. TCPOBOP‐activated mouse CAR was first found to induce CYP2B6 mRNA only when HepG2 cells were treated with a p38 MAPK activator anisomycin (ANI). siRNA knock down of p38 MAPK strongly repressed the induction in HepG2‐derived Ym17 cells, which stably express mouse CAR. Therefore, p38 MAPK signaling can determine CAR‐mediated activation of the CYP2B6 gene. p38 MAPK appeared to target HNF4α in order to determine CYP2B6 promoter activation, since siRNA knockdown of HNF4α profoundly repressed the increase of CYP2B6 mRNA by co‐treatment with ANI and TCPOBOP in Ym17 cells. In addition to CYP2B6 mRNA, ANI co‐treatment with TCPOBOP increased CYP2C9, but not CYP3A4 mRNA, in Ym17 cells. p38 MAPK is substantially activated in mouse primary hepatocytes and an inhibition of p38 MAPK by SB239063 suppressed Cyp2b10 induction by TCPOBOP in the hepatocytes. p38 MAPK may be the cell signaling gate through which CAR selectively determines its target genes and subsequent metabolic consequences.