Effects of o, p′-DDT on the 2,3,7,8-tetrachlorodibenzo- p-dioxin-inducible CYP1A1 expression in murine Hepa-1c1c7 cells

Abstract

Cultured mouse hepatoma Hepa-1c1c7 cells were treated with o, p′-DDT and/or 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) to assess the role of o, p′-DDT on CYP1A1 expression. o, p′-DDT alone did not affect CYP1A1-specific 7-ethoxyresorufin O-deethylase (EROD) activity. In contrast, TCDD-inducible EROD activities were markedly reduced on concomitant treatment with TCDD and o, p′-DDT in a dose-dependent manner. Treatment with ICI 182.780, an estrogen-receptor antagonist, did not affect the suppressive effects of o, p′-DDT on TCDD-inducible EROD activity. TCDD-inducible CYP1A1 mRNA levels were markedly suppressed on treatment with TCDD and o, p′-DDT, and this was consistent with their effects on EROD activity. A transient transfection assay using dioxin-response element (DRE)-linked luciferase and an electrophoretic mobility shift assay revealed that o, p′-DDT reduced the transformation of the aryl hydrocarbons (Ah) receptor to a form capable of specifically binding to the DRE sequence in the promoter region of the CYP1A1 gene. These results suggest that the downregulation of CYP1A1 gene expression by o, p′-DDT in Hepa-1c1c7 cells might be an antagonism of the DRE binding potential of the nuclear Ah receptor but is not mediated through the estradiol receptor.