Induction of cytochrome P450 1A1 gene expression by a vitamin K-3 analog in mouse hepatoma Hepa-1c1c7 cells

Nine vitamin K-3 analogs were compared with respect to the induction of the cytochrome P450 1A1 (CYP1A1) expression in mouse hepatoma Hepa-1c1c7 cells . 6-(4-Diethylamino)phenyl-7-chloro-5,8-quinolinedione (EA4) caused a signi ficant induction of the CYP1A1-mediated ethoxyresorufin O-deethylase activi ty in a time- and concentration-dependent manner. The induction was accompa nied by an increase of the Cyp1a1 mRNA transcription. The transient express ion of the mouse Cyp1a1-CAT gene into cells showed that EA4 induced CAT act ivity. However, the aryl hydrocarbon receptor and its nuclear partner, aryl hydrocarbon receptor nuclear translocator mRNA transcription, were unaffec ted by the EA4 treatment. When the cells were incubated with EA4 in the pre sence of 1 nM TCDD, the ethoxyresorufin O-deethylase activity that was indu ced by TCDD was significantly suppressed by EA4. Inhibition of protein synt hesis by cycloheximide strongly enhanced the EA4-dependent Cyp1a1 mRNA expr ession. Up-regulation of protein kinase C by a 2 h preincubation with phorb ol 12-myristate 13-acetate increased the EA4-dependent expression of the Cy p1a1 gene. In human cells, such as HepG2 (human hepatocarcinoma), MCF-7 (hu man breast adenocarcinoma cell line), and HL-60 (human promyelocytic cell l ine), the expression of CYP1A1 mRNA was also induced by EA4 treatment. More over, CYP1B1 mRNA was increased by EA4 in MCF-7 cells. These results indica te that EA4 modulates CYP1A1 and CYP1B1 expressions by transcriptional acti vation. Also, protein kinase C may be involved in the induction mechanism o f CYP1A1 by EA4.