Receptor-xenobiotic interactions

Receptors are macromolecular binding sites for low molecular weight molecules (ligands), such as hormones and neurotransmitters. As such they are crucial to the well-being of the body. Xenobiotic ligands bind with receptors and in doing so interrupt the normal functioning of the body. 

The xenobiotic may bind with a receptor and thereby block the site from receiving the normal ligand. 

The binding of the toxic ligand may mimic the normal ligand and initiate a deleterious effect. 

The xenobiotic may bind to a site adjacent to that where the endogenous molecule binds, causing the complex to be sterically distorted and resulting in changes that affect the normal functioning of the receptor. 

Macromolecules in the body that normally do not act as receptors may bind xenobiotics and thereby induce physiological changes. 

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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... 

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. 

Receptor-xenobiotic interactions have been associated with immune, central nervous (CNS), endocrine, cardiovascular (CVS), developmental, and reproductive system effects as well as with carcinogenesis. A sampling of toxic chemicals that bind with receptors and their effects is listed in Table 4.3. 

The subject of receptor-xenobiotic interaction is addressed further in subsequent chapters. 

The site at which the xenobiotic interacts with the organism at the molecular level is particularly important. This receptor molecule or site of action may be the nucleic acids, specific proteins within nerve synapses or present within the cellular membrane, or it can be very nonspecific. Narcosis may affect the organism not by interaction with a particular key molecule but by changing the characteristics of the cell membrane. The particular kind of interaction determines whether the effect is broad or more specific within the organism and phylogenetically. 

Proteins and peptides are the natural ligands for many receptors involved in disease. In the future we will likely have modified small molecule xenobiotics which act as agonists or antagonists at these receptors. But, in the meantime, it is necessary to understand the receptor-ligand interactions and signal-transduction mechanisms by which biotechnologically-derived products exert their beneficial and adverse effects. 

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]. 

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. 

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. 

Figure 14.1 Schematic of olfactory sensillum and a generalized biochemical pathway of odor reception. A An olfactory sensillum includes 2-3 neurons surrounded by 3 support cells olfactory dendrites/cilia project up the fluid filled lumen of a cuticular hair. The sensillum lumen is isolated from hemolymph by a cellular barrier. Modified from Steinbrecht (1969) see Steinbrecht (1999) for more details. B Hydrophobic odor molecules enter the aqueous sensillum lumen via pores penetrating the cuticular hair wall. Hydrophilic OBPs are proposed to bind and transport odors to receptor proteins located in the neuronal membranes. ODEs (pathway I) in the sensellum lumen are proposed to degrade these odor molecules. Cytoplasm of support cells contain xenobiotic inactivating enzymes, such as glutathione-S-transferase (GST) (pathway I la) which may also serve to inactivate odor molecules (pathway lib). Interactions between OBPs and ORs and the function of SNMP are unclear. Modified from Rogers et al. (1999).

The AhRR may stand as a unique repressor of DME induction by xenobiotics. No analogous inducible repressor is known to squelch DME induction by other nuclear receptors. However, members of the steroid receptor superfamily such as CAR, GR, LXR, PXR, etc., exhibit complex inhibitory or synergistic interactions because they alter each other s expression or because they compete for generic dimerization partners such as RXR. 

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