Signal transduction-mediated CYP1A1 induction by omeprazole in human HepG2 cells.
Benzimidazole compounds, such as omeprazole and thiabendazole, are a different type of CYP1A1-inducer from Ah receptor-ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 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 CYP 1A1 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, 3'-methoxy-4'-aminoflavone (1 microM), did not inhibit the induction of CYP1A1 produced in HepG2 cells by omeprazole or alpha-naphthoflavone (50 microM), but this antagonist did inhibit that produced by TCDD. Thus, omeprazole appears to induce CYP1A1 by initiating a protein tyrosine kinase-mediated signal transduction pathway, a different pathway from that initiated by TCDD.
Kikuchi
H
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Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Hossain
A
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D001571:Benzoflavones / Q000494:pharmacology; D016227:Benzoquinones; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D047029:Lactams, Macrocyclic; D008113:Liver Neoplasms; D009853:Omeprazole / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; 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; D019833:Genistein; D019363:Cytochrome P-450 CYP1A1; D011505:Protein-Tyrosine Kinases; D009853:Omeprazole