Induction of cytochrome P-450 1A1 by omeprazole in human HepG2 cells is protein tyrosine kinase-dependent and is not inhibited by alpha-naphthoflavone.
Benzimidazole compounds, such as omeprazole and thiabendazole, are a different type of CYP1A1 inducer from Ah receptor-ligands, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and 3-methylcholanthrene. In HepG2 cells, the commonly used tyrosine kinase inhibitors, herbimycin-A and a series of tyrphostins, inhibited the induction of CYP1A1 produced by treatment with TCDD. Genistein, another type of tyrosine kinase inhibitor, inhibited the induction of CYP1A1 whether it was produced by omeprazole or TCDD; however, this inhibition was caused by a dual effect of genistein, that is an anti-tyrosine kinase and an anti-topoisomerase I effect. An antagonist of Ah receptor, alpha-naphthoflavone (0.1-10 microM), and 3'-methoxy-4'-aminoflavone (1 microM), did not inhibit the induction of CYP1A1 produced in HepG2 cells by omeprazole, but both of them did inhibit that produced by TCDD. In one of a number of human lung tumor cell lines, S6T, the inducibility of CYP1A1 was high by TCDD, whereas the inducibility by omeprazole was low. Thus, omeprazole appears to induce CYP1A1 by initiating a protein tyrosine kinase-mediated signal transduction pathway, a different pathway from that inhibited by TCDD.
Research Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan. hkikuchi@idac.tohoku.ac.jp
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D001571:Benzoflavones / Q000494:pharmacology*; D016227:Benzoquinones; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic; D008175:Lung Neoplasms / Q000201:enzymology; D009853:Omeprazole / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured
D001571:Benzoflavones; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D000072317:Polychlorinated Dibenzodioxins; D011809:Quinones; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D017828:Rifabutin; C011512:alpha-naphthoflavone; C020754:herbimycin; D019363:Cytochrome P-450 CYP1A1; D011505:Protein-Tyrosine Kinases; D004264:DNA Topoisomerases, Type I; D009853:Omeprazole