Toxicant-receptor interactions

TOXICANT-RECEPTOR INTERACTIONS MODULATION OF SIGNAL TRANSDUCTIONS AND GENE EXPRESSION Michael S. Denison and William G. Helferich, editors, 256pp., 1998... 

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

Mailman RB, Lawler CP. Toxicant receptor interactions fundamental principles. In Hodgson E, Smart RC, eds. Introduction to Biochemical Toxicology. 3rd ed. New York Wiley, 2001. 

In understanding the kinds of processes by which toxic substances harm an organism, it is important to understand the concept of receptors.9 Here a receptor is taken to mean a biochemical entity that interacts with a toxicant to produce some sort of toxic effect. Generally receptors are macromolecules, such as proteins, nucleic acids, or phospholipids of cell membranes, inside or on the surface of cells. In the context of toxicant-receptor interactions, the substance that interacts with a receptor is called a ligand. Ligands are normally relatively small molecules. They may be endogenous, such as hormone molecules, but in discussions of toxicity are normally regarded as xenobiotic materials. 

The function of a receptor depends on its high specihcity for particular ligands. This often involves the stereochemical ht between a ligand and a receptor, the idea of a lock and key, similar to the interaction of enzymes with various substrates. It should be noted, however, that toxicant-receptor interactions are often around 100 times as strong as enzyme-substrate interactions. Furthermore, whereas an enzyme generally alters a substrate chemically (such as by hydrolysis), a toxicant does not usually change the chemical nature of a receptor other than binding to it. In... 

The four mechanisms listed above involve direct interaction of a toxicant with a receptor in such cases, the toxicant-receptor interaction is likely to be involved in the mechanism of action. In many cases, toxicants may affect receptor function indirectly. For example, in the nervous system, decreases in synaptic transmission (by receptor blockade or damage to a neuron) may lead to increases in the number of receptors on the target neuron (so-called upregulation). This is often felt to be one of the compensatory mechanisms by which the nervous system responds to such perturbation. Conversely, increases in synaptic transmission (e.g., by long-term receptor activation) may lead to compensatory decreases (downregulation) in receptor number. The techniques by which such mechanisms are studied are described later in this chapter. It should be noted that the availability of molecular probes now permits evaluation not only of the characteristics of the binding sites, but also of the expression of the mRNA for the receptor(s) under study. 

Figure 19.3. Simplest model of how toxicant-receptor interactions can lead to functional consequences.

As we did with fractional occupancy, we can predict the data that would result from a toxicant-receptor interaction that was modeled by Eq. (19.14). Let s see what theoretical data would look like if we assume (for the sake of easy calculations) that the Bmax = 100 and the KD = 1 nM. (This is a similar exercise to what we did with fractional occupancy.) Picking arbitrary [F] concentrations, Table 19.3 shows the derived values [try this yourself using Eq. (19.14)]. 

Denison MS, Elferink CF, Phelan D. 1998. The Ah receptor signal transduction pathway. In Toxicant-Receptor Interactions in the Modulation of Signal Transduction and Gene Expression, ed. MS Denison, WG Helferich, pp. 3-33. Philadelphia Taylor Francis... 

Toxicant-receptor interactions. Taylor and Francis, Philadelphia, PA, USA, 69-99. Vinggaard A.M., Hnida C. and Larsen J.C., 2000. Toxicology, 145, 173. 

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