Methoxychlor suppresses the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible CYP1A1 expression in murine Hepa-1c1c7 cells.
Methoxychlor (MXC) is a pesticide that was developed as a replacement for dichlorodiphenyltrichloroethane (DDT). The influence of MXC on CYP1A1 expression or the functions of mouse hepatoma Hepa-1clc7 remain unclear. Cultured Hepa-1c1c7 cells were treated with MXC with or without 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to assess the role of MXC on CYP1A1 expression. MXC alone did not affect CYP1A1-specific 7-ethoxyresorufin O-deethylase (EROD) activity. In contrast, TCDD-inducible EROD activities were markedly reduced upon concomitant treatment with TCDD and MXC in a concentration-dependent manner. Treatment with ICI 182.780, an estrogen-receptor antagonist, did not affect the suppressive effects of MXC on TCDD-inducible EROD activity. TCDD-inducible CYP1A1 mRNA levels were markedly suppressed upon treatment with TCDD and MXC, and this is 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 MXC 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 MXC 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.
Han
Eun Hee
EH
BK21 Project Team, Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju, Republic of Korea.
Jeong
Tae Cheon
TC
Jeong
Hye Gwang
HG
D000818:Animals; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D052244:Endocrine Disruptors / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity*; D008731:Methoxychlor / Q000633:toxicity*; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000502:physiology
D052244:Endocrine Disruptors; D007306:Insecticides; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D008731:Methoxychlor