Characterization of human CYP1A1/1A2 induction by DNA microarray and alpha-naphthoflavone.
DNA microarrays and real time PCR were used to analyze the mechanism of gene induction by CYP1A1 inducers, beta-naphthoflavone, and omeprazole, in the human hepatocellular carcinoma HepG2 cells. Reproducible and significant inductions were observed in a limited number of genes including CYP1A1 and CYP1A2. Genes induced by omeprazole included several protein tyrosine kinase targets. This result confirmed that omeprazole could modulate gene expressions through protein tyrosine kinase-mediated pathway. Induction ratios were considerably different from CYP1A1 and CYP1A2 (>10-fold) to other induced genes (<5-fold). alpha-Naphthoflavone, which is known as an antagonist to 2,3,7,8-tetrachlorodibenzo-p-dioxin, inhibited the inductions of heme oxygenase 1, glutamate-cysteine ligase (modifier unit), and thioredoxin reductase by beta-naphthoflavone but not those of CYP1A1 and CYP1A2. It unexpectedly enhanced the beta-naphthoflavone-mediated CYP1A1 and CYP1A2 induction. These results suggest that the CYP1A1 and CYP1A2 genes, which share their 5(') enhancer regions, are regulated differently from the other genes.
Ishida
Seiichi
S
Project Team for Pharmacogenetics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, 158-8501, Tokyo, Japan. ishida@nihs.go.jp
Jinno
Hideto
H
Tanaka-Kagawa
Toshiko
T
Ando
Masanori
M
Ohno
Yasuo
Y
Ozawa
Shogo
S
Sawada
Jun ichi
Ji
D000943:Antigens, Differentiation / Q000378:metabolism; D001483:Base Sequence; D001571:Benzoflavones / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D017931:DNA Primers; D037502:Galectin 3; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009853:Omeprazole / Q000378:metabolism / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015533:Transcriptional Activation
D000943:Antigens, Differentiation; D001571:Benzoflavones; D017931:DNA Primers; D037502:Galectin 3; D017395:Plasminogen Activator Inhibitor 1; C011512:alpha-naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D011505:Protein-Tyrosine Kinases; D009853:Omeprazole