title: Structural and mechanistic aspects of transcriptional induction of cytochrome P450 1A1 by benzimidazole derivatives in rat hepatoma H4IIE cells.
abstract: The effect of several structurally different benzimidazole compounds on CYP1A1 expression at the transcriptional, mRNA and protein levels was investigated in the rat hepatoma H4IIE cell line. Omeprazole, thiabendazole, carbendazim, 2-mercaptobenzimidazole and 2-mercapto-5-methoxybenzimidazole caused a dose-dependent increase in CYP1A1 protein levels that reached maximum effect at 250 microm, as measured by Western blot. In addition, hydroxyomeprazole, 2-aminobenzimidazole and 2-mercapto-5-nitro-benzimidazole caused a notable increase in CYP1A1 protein expression, whereas 5-O-desmethylomeprazole, 2-hydroxybenzimidazole, 2-benzimidazole propionic acid and 5-benzimidazole carboxylic acid were ineffective. Thus, benzimidazole substituted with a thiol or an amino group in the 2-position were active inducers. Northern blot analysis confirmed an extensive increase of CYP1A1 mRNA induced by omeprazole and 2-mercapto-5-methoxybenzimidazole which was 32% and 49% of maximal induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) respectively, whereas thiabendazole and carbendazim showed approximately 15% increase as compared to TCDD. Transient transfection of H4IIE cells, with a XRE-pGL3 reporter gene construct revealed a 2.3-4.3-fold induction by carbendazim, thiabendazole, and 2-mercapto-5-methoxybenzimidazole as compared to a 3.3- and 23-fold induction by omeprazole and TCDD, respectively. Thus, these data indicate that the benzimidazoles utilize the aryl hydrocarbon receptor-arnt-XRE-mediated signal-transduction pathway for induction of the CYP1A1 gene.
authors: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. maria.backlund@imm.ki.se
authors: M
authors: M
authors: Backlund
authors: L
authors: L
authors: Weidolf
authors: M
authors: M
authors: Ingelman-Sundberg
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002219:Carbamates; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism; D009853:Omeprazole / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013827:Thiabendazole / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D001562:Benzimidazoles; D002219:Carbamates; D012333:RNA, Messenger; C030698:2-mercaptobenzimidazole; D019363:Cytochrome P-450 CYP1A1; C006698:carbendazim; D009853:Omeprazole; D013827:Thiabendazole