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1-amino-3,7,8-trichlorodibenzo-p-dioxin: a specific antagonist for TCDD-induced myelotoxicity
Abstract:
It was recently reported that suppression of murine bone marrow hematopoiesis is a very sensitive indicator for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity (1). We report here that a structural analog of TCDD, 1-NH2-3,7,8-trichlorodibenzo-p-dioxin (NH2-TriCDD), is a specific and effective antagonist for TCDD-induced myelotoxicity and enzyme induction. When administered to mice or added directly into culture at a 100-fold excess, relative to TCDD, NH2-TriCDD completely abrogated the ability of TCDD to inhibit granulocyte-macrophage progenitor cells (CFU-C) formation, an indicator of hematopoiesis. Further, NH2-TriCDD inhibited TCDD-induced activation of cytochrome P1-450 monooxygenase activity. Studies designed to measure specific binding of TCDD to the cytosolic Ah receptor indicated that NH2-TriCDD effectively inhibited binding of TCDD to the receptor by acting as a competitive antagonist (Ki = 0.72 nM).
Insights
1-NH2-3,7,8-trichlorodibenzo-p-dioxin (NH2-TriCDD) effectively blocks 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. This dioxin analog prevents TCDD-induced bone marrow suppression and enzyme activation by competitively inhibiting TCDD binding to the Ah receptor.
Area of Science:
- Toxicology
- Molecular Biology
- Pharmacology
Background:
- Murine bone marrow hematopoiesis suppression is a sensitive indicator of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity.
- TCDD induces myelotoxicity and cytochrome P1-450 monooxygenase activity.
Purpose of the Study:
- To investigate the antagonistic potential of 1-NH2-3,7,8-trichlorodibenzo-p-dioxin (NH2-TriCDD) against TCDD-induced toxicity.
- To determine the mechanism by which NH2-TriCDD exerts its antagonistic effects.
Main Methods:
- Administration of NH2-TriCDD and TCDD to mice.
- In vitro culture assays to assess inhibition of granulocyte-macrophage progenitor cells (CFU-C) formation.
- Measurement of cytochrome P1-450 monooxygenase activity.
- Competitive binding assays to determine the interaction with the cytosolic Ah receptor.
Main Results:
- NH2-TriCDD completely abrogated TCDD-induced inhibition of CFU-C formation when administered in a 100-fold excess.
- NH2-TriCDD inhibited TCDD-induced activation of cytochrome P1-450 monooxygenase activity.
- NH2-TriCDD acted as a competitive antagonist, inhibiting TCDD binding to the Ah receptor with a Ki of 0.72 nM.
Conclusions:
- NH2-TriCDD is a specific and effective antagonist of TCDD-induced myelotoxicity and enzyme induction.
- The antagonistic effect is mediated by competitive inhibition of TCDD binding to the Ah receptor.