Polychlorinated biphenyls and related compound interactions with specific binding sites for thyroxine in rat liver nuclear extracts

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Abstract
Thyroid hormone analogues, polychlorinated biphenyls (PCBs), and their derivatives were shown to bind specifically to thyroxine-specific binding sites in rat liver nuclear extracts. The structure-binding relationship for thyroxine binding prealbumin was qualitatively similar to that for the nuclear receptor. In general for both binding proteins, increased binding affinity was seen for the more linear and in some cases rectangular shaped (as opposed to the angular shaped thyroid hormones) chlorinated aromatic hydrocarbons with chlorine concentrated in lateral positions (3,3'',5,5''-substitution on biphenyl nucleus). However two groups of compounds showed distinct quantitative differences. The relatively less polar and more lipophilic nonhydroxylated PCBs bound the nuclear receptor with significantly lower affinities while two compounds that are structurally related by the potential for equilibrium interconversion to a rigid planar structure bound with significantly higher affinities. This latter class of compounds represents soluble dioxin (TCDD) approximate isosteres and has an extended (polarizable) .pi.-system brought about by a planar structure (or conversion to the same) and lateral halogenation. These structure requirements are maximally expressed in 3,3'',5,5''-tetrachlorodiphenoquinone (TCDQ), which shows a remarkably high affinity (Ka = 1.84 .times. 1011 M-1) for the nuclear receptor. Thus, the nuclear receptor shows the expected structural specificity and sensitivity for possible involvement in the high toxicity of these classes of compounds. The physiological significance of these binding results is supported by the dose-dependent regulation (increase) of the thyroxine nuclear receptor number by dioxin, although the mechanism responsible for this increase is not clear. The nuclear binding component was further analyzed by sucrose density gradient centrifugation and was found to have a sedimentation coefficient of 4.3 S under high salt conditions. A crude estimate of the molecular weight (45,200) was obtained from a linear plot of standard globular protein fraction number (sedimentation coefficient) vs. log molecular weight. Although direct evidence is not provided, the thyroxine nuclear receptor may cooperate with a second receptor in binding the TCDQ type ligand or exists as a multimeric species with binding properties of both prealbumin and the dioxin (or Ah) receptor.

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