ANTAGONISM OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) - INDUCED CYP1A1 GENE-EXPRESSION BY 6-METHYL-1,3,8-TRICHLORODIBENZOFURAN (MCDF) - MECHANISTIC STUDIES uri icon

abstract

  • Treatment of rat hepatoma H-4-II E cells with 10-9 M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in maximal induction of cytochrome P4501A1-dependent ethoxyresorufin O-deethylase (EROD) activity. In contrast, 10-6 M 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was relatively inactive as an inducer. Cotreatment with TCDD (10-9 M) and MCDF (10-8, 10-7, 10-6 M) resulted in a concentration-dependent antagonism of EROD induction. In addition, MCDF caused a concentration-dependent decrease in TCDD-induced CYP1A1 mRNA levels. In a parallel study, MCDF reduced the accumulation of transcriptionally active nuclear [3H]TCDD:Ah receptor complexes. Receptor competition studies with freshly prepared Sprague-Dawley rat cytosol revealed that MCDF competes with [3H]TCDD for Ah receptor binding sites (EC50 140 nM). These results suggest that MCDF antagonizes TCDD-mediated induction of CYP1A1 gene expression by competition for the Ah receptor and by decreasing the accumulation of transcriptionally active nuclear Ah receptor complexes. 1992.

published proceedings

  • CHEMOSPHERE

author list (cited authors)

  • MERCHANT, M., MORRISON, V., & SAFE, S.

citation count

  • 4

complete list of authors

  • MERCHANT, M||MORRISON, V||SAFE, S

publication date

  • October 1992