Paper Details
- Masashi Sekimoto (Laboratory of Environmental Hygiene, Department of Environmental Science, School of Life and Environmental Science, Azabu University / sekimoto@azabu-u.ac.jp)
1) Laboratory of Environmental Hygiene, Department of Environmental Science, School of Life and Environmental Science, Azabu University , 2) Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka
The effects of six cooked food-derived heterocyclic carcinogenic amines (HCAs), including 2-amino-9H-pyrido[2,3-b]indole acetate (AαC) and its 3-methyl derivative (MeAαC), on cytochrome P450 3A (CYP3A) induction were examined using a human hepatoblastoma cell-derived HPL-A3 cell line, previously established for a luciferase-reporter gene assay for the detection of a CYP3A4 inducer. AαC and MeAαC, but not the four other HCAs, enhanced luciferase activity. Quantitative RT-PCR further confirmed the significant induction of CYP3A4 mRNA by AαC and MeAαC. Since CYP3A4 gene expression is primarily regulated by the pregnane X receptor (PXR) and occasionally by other receptors, such as the aryl hydrocarbon receptor and vitamin D receptor, the effects of siRNAs for these regulator genes on AαC- and MeAαC-mediated increases in luciferase activity were investigated further. PXR siRNA, but not other siRNAs, significantly reduced AαC- and MeAαC-induced luciferase activities. These results demonstrate for the first time that AαC and MeAαC, among the six HCAs tested, increase CYP3A4 mRNA via PXR activation in human hepatoblastoma-derived HPL-A3 cells.