Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase
Open accessAbstract
We previously hypothesized that the genetic trait of aromatic hydrocarbon nonresponsiveness (the failure in certain inbred strains of mice of polycyclic hydrocarbons to induce aryl hydrocarbon hydroxylase activity, and the diminished sensitivity to the more potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is due to mutation which results in an induction receptor with a diminished affinity for the inducing compound. Following the intraperitoneal administration of [14C]TCDD (6 nmol/kg), hepatic accumulation of the radiolabel was greatest in C57BL/6J mice, intermediate in the hybrid B6D2F1/J mice, and least in DBA/2J mice, a pattern which mirrors the strain sensitivity to hydroxylase induction by TCDD (C57BL/6J greater than B6D2F1/J greater than DBA/2J). These data are compatible with receptor mutation theory and suggested that the hepatic uptake of TCDD is determined by the affinity of the receptor. In vitro experiments on the binding of [3H]TCDD to hepatic cytosol from C57BL/6J mice revealed a small pool of high affinity sites which stereospecifically and reversibly bind TCDD. The specific binding of [3H]TCDD to hepatic cytosol had an equilibrium dissociation constant KD of 0.27 nM and a maximum binding capacity of 84 fmol/mg of cytosol protein. Much less high affinity specific binding of [3H]TCDD was observed in hepatic cytosol from DBA/2J mice, but the KD was not estimated because of the limited aqueous solubility of the ligand. The binding affinity of 23 halogenate…
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TCDD and tetrachlorodibenzofuran are of great toxicological significance due to structural similarity to dioxin-like PCBs and ability to bind the same cellular receptor.
“Of particular relevance are tetrachlorodibenzo-p-dioxin (TCDD) and tetrachlorodibenzofuran, which are of great toxicological significance due to their structural similarity to dioxin-like PCBs and their ability to bind to the same cellular receptor (Poland et al., 1976; Yavuz et al., 2023).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Poland et al., 1976
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“…are useful in examining the consequences of Ahrd versus Ahrb on the same background, therefore eliminating the possibility of non-Ahr genomic elements on endpoints such as susceptibility to BaP carcinogenesis and aryl hydrocarbon hydroxylase activity (Poland et al. 1976; Boobis and Nebert 1977).”
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- Authors
- Poland, A., Glover, E., & Kende, A. S.
- Affiliations
- University of Rochester Medicine (US)
- University of Rochester (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1976-08
- Volume
- 251
- Issue
- 16
- Pages
- 4936-4946
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1577296862
- Cited by
- 1,370
- References
- 1
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 26 · 2023: 31 · 2022: 21 · 2021: 36 · 2020: 34 · 2019: 25 · 2018: 21 · 2017: 20 · 2016: 23 · 2015: 21 · 2014: 19 · 2013: 12 · 2012: 17
- FWCI
- 32.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD, aryl hydrocarbon hydroxylase induction, aryl hydrocarbon receptor, receptor mutations, stereospecific binding, high-affinity binding sites, dibenzofuran, polycyclic hydrocarbons, inbred mouse strains, C57BL/6J mice
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Aryl Hydrocarbon Hydroxylases, Binding Sites, Biological Transport, Cytosol, Dioxins, Kinetics, Liver, Mice, Inbred Strains, Proteins, Receptors, Drug, Species Specificity, Structure-Activity Relationship, Temperature, Mice
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