The Study of Receptor-Toxicant Interactions

THE STUDY OF RECEPTOR-TOXICANT INTERACTIONS 19.3.1 Development of Radioligand Binding Assays... 

Herschman HR, Simpson DL, Cawley DB. Toxic ligand conjugates as tools in the study of receptor-ligand interactions. J Cell Biochem 1982 20 163-76. 

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. 

In an animal, a xenobiotic substance may be bound reversibly to a plasma protein in an inactivated form. A polar xenobiotic substance, or a polar metabolic product, may be excreted from the body in solution in urine. Nonpolar substances delivered to the intestinal tract in bile are eliminated with feces. Volatile nonpolar substances such as carbon monoxide tend to leave the body via the pulmonary system. The ingestion, biotransformation, action on receptor sites, and excretion of a toxic substance may involve complex interactions of biochemical and physiological parameters. The study of these parameters within a framework of metabolism and kinetics is called toxicometrics. 

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. 

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