Xenobiotics receptor interactions

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 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. 

Mechanisms for the xenobiotic disruption of hormonal activity. In certain cases the xenobiotic may interact with the hormone receptor in such a manner that a hormonal response is generated. In some instances this hormonal response is inappropriate for the sex or normal breeding state of the organism. In other instances the toxicant may interact with the receptor in such a manner that it binds tightly to the receptor site but does not initiate the conformational changes that confer the normal cellular interactions of the receptor. In this instance the hormone is blocked from interacting with the receptor and the response is blocked. 

Any reproductive toxicant capable of endocrine disruption can also be considered an endocrine-disrupting chemical (EDC) or an endocrine disrupter. Another term frequently used with respect to endocrine disruption, especially regarding xenobiotics that interact with endogenous hormone receptors, is hormonally active agent (HAA). In most instances, "EDC," "endocrine disrupter," or "HAA" can be used interchangeably to discuss the actions of a given xenobiotic (Evans, 2007). 

Sinz, M., Kim, S., Zhu, Z., Chen, T., Anthony, M., Dickinson, K. and Rodrigues, A.D. (2006) Evaluation of 170 xenobiotics as transactivators of human pregnane X receptor (hPXR) and correlation to known CYP3A4 drug interactions. Current Drug Metabolism, 7, 375-388. 

Many non-target organisms (which possess human- and animal-alike metabolic pathways, similar receptors or biomolecules) are inadvertently exposed to these substances [40, 58]. Since several APIs are known to interact with Cytochrome P-450, there is a potential risk of disruption in the homeostasis of non-target organisms. Moreover, pharmaceuticals that interact with the Glycoprotein-P (P-gp), a multidrug transporter that actively transports xenobiotics out of the cell, increase their sensitivity to environmental pollutants [17]. 

Generally, it appears that effects of xenobiotics on organs or endpoints may be similar in children and adults, e.g., liver necrosis observed in adults will also be observed in children. As regards toxicodynamics, age-dependent differences are primarily related to the specific and unique effects that substances may have on the development of the embryo, fetus, and child in that the physiological development of the nervous, immune, and endocrine/reproductive systems continues until adolescence (12 to 18 years). Furthermore, receptors and other molecular targets for various xenobiotics are continuously developing during the embryonic, fetal, and infant periods. This may cause age-dependent differences in the outcome of receptor-xenobiotic interactions and even result in opposite effects of xenobiotics in infants and adults. The available data are insufficient to evaluate... 

It is necessary to appreciate both for a mechanistic view of toxicology. The first of these includes the absorption, distribution, metabolism, and excretion of xenobiotics, which are all factors of importance in the toxic process and which have a biochemical basis in many instances. The mode of action of toxic compounds in the interaction with cellular components, and at the molecular level with structural proteins and other macromolecules, enzymes, and receptors, and the types of toxic response produced are included in the second category of interaction. However, a biological system is a dynamic one, and therefore a series of events may follow the initial response. For instance, a toxic compound may cause liver or kidney damage and thereby limit its own metabolism or excretion. 

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. 

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