CCAAT/enhancer binding protein activation by PD98059 contributes to the inhibition of AhR-mediated 3-methylcholanthrene induction of CYP1A1.
2'-Amino-3'-methoxyflavone (PD98059), an MKK1 inhibitor, negatively regulates the induction of the CYP1A1 gene by polycyclic aromatic hydrocarbons. In view of the observations that PD98059 inhibits AhR-mediated CYP1A1 induction and has the capability to activate C/EBPbeta, the study investigated whether the inhibition by PD98059 of 3-MC induction of CYP1A1 results from C/EBP activation. 3-MC induction of the CYP1A1 and the CYP1A1 promoter-luciferase gene were inhibited by treatment of H4IIE cells with PD98059. PD98059 treatment inhibited 3-MC-induced AhR binding to the XRE, but increased protein binding to the CYP1A1 C/EBP binding site. PD98059 inhibited 3-MC induction of CYP1A1 in cells stably transfected with a dominant negative mutant of MKK1, indicating that PD98059 represses CYP1A1 induction by 3-MC irrespective of its MKK1 inhibition. The role of C/EBP activation by PD98059 in repressing CYP1A1 induction was supported by the observation that a dominant-negative mutant C/EBP abolished the ability of PD98059 to suppress 3-MC induction of CYP1A1.
Shin
S M
SM
National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of South Korea.
Cho
I J
IJ
Kim
S G
SG
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D008748:Methylcholanthrene / Q000008:administration & dosage*; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; D005419:Flavonoids; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D008748:Methylcholanthrene; D019363:Cytochrome P-450 CYP1A1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one