Time-dependent transcriptional induction of CYP1A1, CYP1A2 and CYP1B1 mRNAs by H+/K+ -ATPase inhibitors and other xenobiotics.
1. Xenobiotic-mediated regulation of mRNA expression of all members of the human cytochrome P450 (CYP) 1 family has been measured by RT-PCR in the hepatoma cell line, HepG2. Besides the positive control beta -naphthoflavone, the H(+)/K(+)-ATPase inhibitors omeprazole, lansoprazole, pantoprazole and rabeprazole and the anti-malaria drug primaquine were included in this study. 2. beta-Naphthoflavone, primaquine, omeprazole and lansoprazole increased mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Induction by rabeprazole was significant only for CYP1A1 and CYP1A2, whereas none of the CYP1 mRNAs was induced by pantoprazole. This result was confirmed in primary human hepatocytes. 3. Transcriptional regulation was proved by inhibition of induction with actinomycin D. 4. Increase of CYP1 mRNA was significant after 1 h and maximal after 4 h. CYP1B1, but not CYP1A1 or CYP1A2, was dramatically down-regulated between 4 and 24 h. This decrease was prevented by treatment of cells with actinomycin D after induction, indicating an active transcription-dependent mechanism of CYP1B1 mRNA degradation. 5. In conclusion, xenobiotics inducing CYP1A1 mRNA expression have been shown also to induce CYP1A2 and CYP1B1, differing only with regard to level and time course of induction.
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Institute of Clinical Pharmacology, Charité, Humboldt University of Berlin, Schumannstr. 20/21, D-10098 Berlin, Germany. s.krusekopf@gmx.de
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D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065633:Cytochrome P-450 CYP1B1; D017931:DNA Primers; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015262:Xenobiotics / Q000494:pharmacology*
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D017931:DNA Primers; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D015262:Xenobiotics; D003609:Dactinomycin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1