Differences in inducibility of CYP1A1-mRNA by benzimidazole compounds between human and mouse cells: evidences of a human-specific signal transduction pathway for CYP1A1 induction.
Three benzimidazole compounds, omeprazole (OP), thiabendazole (TBZ), and lansoprazole (LP), were compared with respect to the induction of CYP1A1-mRNA in human hepatoma cells, HepG2. OP was the most potent inducer among the three compounds, but LP was found to be a weak inducer. Induction by TBZ was at an intermediate level. None of these compounds induced CYP1A1-mRNA in a mouse hepatoma cell line, Hepa-1. The transient expression of mouse Cyp1a1-CAT gene into HepG2 cells showed that OP treatment of the transfectants induced CAT activity to the same degree as 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Therefore, the cellular factors in human cells were able to work on the mouse regulatory element. The expression of human aryl hydrocarbon (Ah) receptor in the mouse Hepa-1 mutant cell line cl-19, which is defective in Ah receptor, did not increase the induction level of CYP1A1-mRNA by OP treatment. When the cultured medium of HepG2 cells in the presence of OP was added to the mouse Hepa-1 cell culture medium, CYP1A1-mRNA was not induced in Hepa-1 cells. It is thus concluded that metabolites of OP in human cells are not the ligands for the human Ah receptor. Therefore, in human cells, but not mouse cells, there must be an OP-sensitive activation factor for the human Ah receptor.
Institute of Development, Aging, and Cancer, Division of Gene Research, Tohoku University, Sendai, Japan. hkikuchi@idac.tohoku.ac.jp
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Kikuchi
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Kato
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Mizuno
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Hossain
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Ikawa
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Miyazaki
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Watanabe
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D017931:DNA Primers; D018076:DNA, Complementary; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D064747:Lansoprazole; D008113:Liver Neoplasms; D008114:Liver Neoplasms, Experimental; D051379:Mice; D009853:Omeprazole / Q000031:analogs & derivatives / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D013045:Species Specificity; D013827:Thiabendazole / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D017931:DNA Primers; D018076:DNA, Complementary; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011993:Recombinant Fusion Proteins; D064747:Lansoprazole; D019363:Cytochrome P-450 CYP1A1; D015500:Chloramphenicol O-Acetyltransferase; D009853:Omeprazole; D013827:Thiabendazole