tailieunhanh - Báo cáo khoa học: Modulation of aryl hydrocarbon receptor transactivation by carbaryl, a nonconventional ligand

Carbaryl (1-naphthyl-N-methylcarbamate), a widely used carbamate insecti-cide, induces cytochrome P450 1A gene expression in mammalian cells. This activity is usually mediated by the interaction of the compound with the aryl hydrocarbon receptor. | ỊFEBS Journal Modulation of aryl hydrocarbon receptor transactivation by carbaryl a nonconventional ligand Susanna Boronat1 Susana Casado2 Jose M. Navas2 and Benjamin Pina1 1 Institut de Biologia Molecular de Barcelona Consejo Superior de Investigaciones Cientificas Barcelona Spain 2 Department of Environment Instituto Nacionalde Investigacion y Tecnolog a Agraria y Alimentaria INIA Madrid Spain Keywords bioassays dioxin-like endocrine disruptors recombinant yeast assays transcriptional response Correspondence B. Pina IBMB-CSIC Jordi Girona 18 08034 Barcelona Spain Fax 34 93 204 59 04 Tel 34 93 400 61 57 E-mail bpcbmc@ Received 2 March 2007 revised 2 May 2007 accepted 3 May 2007 doi Carbaryl 1-naphthyl-N-methylcarbamate a widely used carbamate insecticide induces cytochrome P450 1A gene expression in mammalian cells. This activity is usually mediated by the interaction of the compound with the aryl hydrocarbon receptor. However it has been proposed that this mechanism does not apply to carbaryl because its structure differs from that of typical aryl hydrocarbon receptor ligands. We show here that carbaryl promotes activation of target genes in a yeast-based bioassay expressing both aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator. By contrast carbaryl acted as a competitive inhibitor rather than as an agonist in a simplified yeast system in which aryl hydrocarbon receptor nuclear translocator function is bypassed by fusing aryl hydrocarbon receptor to a heterologous DNA binding domain. This dual action of carbaryl agonist and partial antagonist was also observed by comparing carbaryl response in two vertebrate cell lines. A yeast two-hybrid assay showed that the mammalian coactivator cAMP response element-binding protein readily interacts with aryl hydrocarbon receptor bound to its canonical ligand p-naphthoflavone but not with the carbaryl-aryl hydrocarbon receptor complex. We propose that .

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