Synthesis and aryl hydrocarbon receptor binding properties of radiolabeled polychlorinated dibenzofuran congeners
Microchlorination of 1,4,9(/sup 3/H)dibenzofuran gave several polychlorinated dibenzofuran (PCDF) products and 2,3,7,8-(/sup 3/H)tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-(/sup 3/H)pentachlorodibenzofuran (PeCDF), and 1,2,3,6,7,8-/1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) of high specific activity (57, 34, and 32.5 Ci/mmol, respectively) were purified by preparative high-pressure liquid chromatography. These compounds were investigated as radioligands for the rat liver cytosolic aryl hydrocarbon (Ah) receptor protein. Like 2,3,7,8-(/sup 3/H)tetrachlorodibenzo-p-dioxin (TCDD), the radiolabeled PCDF congeners exhibited saturable binding with the receptor protein and sucrose density gradient analysis of the radiolabeled ligand-receptor complexes gave specific binding peaks with comparable sedimentation profiles. The rank order of radioligand binding affinities (Kd values) was 2,3,7,8-TCDD greater than 2,3,7,8-TCDF greater than 1,2,3,6,7,8-HCDF greater than 1,2,3,7,8-PeCDF and the maximum difference in Kd values for the four radioligands was less than 13-fold (0.44-5.9 nM). The interactions of the PCDF radioligands with the cytosolic receptor all exhibited saturable binding curves and linear Scatchard plots and the slopes of their Hill plots were in the range 1.0-1.1, thus indicating that cooperativity was not a factor in these binding interactions. The relative stabilities and dissociation kinetics of the radioligand-receptor complexes were highly dependent on the structure of the radioligand. The dissociation curves of the 2,3,7,8-(/sup 3/H)TCDD and PCDF receptor complexes were biphasic and this suggests that there may be a temporal shift in ligand binding affinities. However, the rates of dissociation did not correlate with the rank order of ligand binding affinities.
- Research Organization:
- Texas A and M Univ., College Station
- OSTI ID:
- 5601303
- Journal Information:
- Arch. Biochem. Biophys.; (United States), Vol. 259:1
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
BENZOFURANS
CHLORINATION
CHLORINATED AROMATIC HYDROCARBONS
BIOCHEMICAL REACTION KINETICS
STRUCTURE-ACTIVITY RELATIONSHIPS
AFFINITY
LIGANDS
LIQUID COLUMN CHROMATOGRAPHY
LIVER
RATS
RECEPTORS
TRITIUM COMPOUNDS
ANIMALS
AROMATICS
BODY
CHEMICAL REACTIONS
CHROMATOGRAPHY
DIGESTIVE SYSTEM
FURANS
GLANDS
HALOGENATED AROMATIC HYDROCARBONS
HALOGENATION
HETEROCYCLIC COMPOUNDS
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PROTEINS
REACTION KINETICS
RODENTS
SEPARATION PROCESSES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550201 - Biochemistry- Tracer Techniques