Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

Pharmacol Ther. 1995;67(2):247-81. doi: 10.1016/0163-7258(95)00017-b.

Abstract

The aryl hydrocarbon (Ah) receptor binds several different structural classes of chemicals, including halogenated aromatics, typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polynuclear aromatic and heteropolynuclear aromatic hydrocarbons. TCDD induces expression of several genes including CYP1A1, and molecular biology studies show that the Ah receptor acts as a nuclear ligand-induced transcription factor that interacts with xenobiotic or dioxin responsive elements located in 5'-flanking regions of responsive genes. TCDD also elicits diverse toxic effects, modulates endocrine pathways and inhibits a broad spectrum of estrogen (17 beta-estradiol)-induced responses in rodents and human breast cancer cell lines. Molecular biology studies show that TCDD inhibited 17 beta-estradiol-induced cathepsin D gene expression by targeted interaction of the nuclear Ah receptor with imperfect dioxin responsive elements strategically located within the estrogen receptor-Sp1 enhancer sequence of this gene.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Aldehyde Dehydrogenase / drug effects
  • Aldehyde Dehydrogenase / genetics
  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Base Sequence
  • Breast Neoplasms / pathology
  • Cathepsin D / genetics
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Estradiol / pharmacology
  • Estrogen Antagonists / metabolism
  • Estrogen Antagonists / toxicity
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / genetics
  • Glutathione Transferase / drug effects
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • Molecular Sequence Data
  • Polychlorinated Dibenzodioxins / metabolism
  • Polychlorinated Dibenzodioxins / toxicity*
  • Rats
  • Receptors, Aryl Hydrocarbon / drug effects*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • Transcription Factors / drug effects
  • Transcription Factors / genetics
  • Tumor Cells, Cultured

Substances

  • Estrogen Antagonists
  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Transcription Factors
  • Estradiol
  • Cytochrome P-450 Enzyme System
  • Aldehyde Dehydrogenase
  • Glutathione Transferase
  • Cathepsin D