Specificity of the Hormone-Receptor Interaction

As noted above, closely related isomers of DDD and DDT had very different abilities to inhibit binding to the alligator ER. Two factors are involved. First is the conformation of the receptor, and the second is the three-dimensional structure of the xenobiotic and its resemblance to a natural ligand. As a model system to investigate the structure-activity relationships of molecules that react to specific sites in hormones, we will use the well-studied molecules 1,3,7,8 TCDD (dioxin) and various PCBs. 

Dioxin and PCBs are hypothesized to be toxic because of three modes of action (McKinney and Waller 1994). First, these compounds are toxic due to their irreversible chemical reactivity in binding to a variety of macromolecules such as DNA. Second, these compounds are highly lipid soluble and may accumulate in lipid-rich cellular components. Third, these compounds can reversibly react to specific sites in receptors and enzymes. Overall toxicity is certainly due to a combination of these items although we will concentrate on the third mode of action. 

8 TCDD is often regarded as a highly toxic material. However, that toxicity is in one manner very specific. Table 5.3 presents data for the toxicity of TCDD to a variety of invertebrate species. Unlike the common perception, TCDD is not particularly toxic to a wide range of invertebrates. At relatively high concentrations and particularly body burdens and for a significant duration of exposure, the TCDD had little or no effect. Conversely, Table 5.4 presents data for several vertebrate species. At concentrations hundreds or even a thousand times less than those for the invertebrate species, the mortality was 100%. Obviously, vertebrates have something that invertebrates do not. 

Vertebrates apparently have a specific protein, the aryl hydrocarbon (Ah) receptor, that has a great affinity for 2,3,7,8 TCDD. Although a functionally similar receptor no doubt exists in invertebrates, the vertebrate receptor has a great affinity for dioxin. Given that vertebrates and invertebrates have diverged more than 500 million years ago, it is ironic that an evolutionary event of the Cambrian determines the pattern of toxicity to compounds not formed until the 20th century. 

Test Species Water Cone. (ng/l)a Organism Cone. (pg/g)b Duration of Exposure Effects 

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The objective of such studies is to measure the affinity, capacity and specificity of the hormone-receptor interaction [3, 7], Measurements of affinity and capacity are... 

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