Endogenous chemicals

By the turn of the century the theory of chemical mediation of physiologic responses had gained some currency. There ensued in some laboratories an intense search for endogenous chemical modifiers of bodily responses. The first such agent to be isolated from mammalian tissue was the ubiquitous hormone, epinephrine—at that time known as adrenaline. This compound has played an important role in pharmacology as well as in medicinal chemistry. 

The basis for believing the pharmacological intervention can be a major approach to the treatment of disease is the fact that the body generally functions in response to chemicals. Table 1.1 shows partial lists of hormones and neuro transmitters in the body. Many more endogenous chemicals are involved in normal physiological function. The fact that so many physiological processes are controlled by chemicals provides... 

Some endogenous chemicals controlling normal physiological function. 

Of the several classes of receptors for endogenous chemical signals [3], two are used as postsynaptic receptors in synaptic transmission ligand-gated ion channels (LGICs) and G protein-coupled receptors (GPCRs Fig. 1). Due to the large number of transmitters and the existence of several receptor types for almost all, postsynaptic receptor activation is the most diversified step of synaptic transmission. Table 1 shows selected neurotransmitter receptors. 

Antagonist. A compound that is able to bind to a drug or endogenous chemical s receptors and block them. Hence, it competes with the dmg/... 

Table 8.1 Endogenous Chemicals Activating or Sensitizing Nociceptors... 

Bronchoconstriction is also elicited by several endogenous chemicals released from mast cells during an allergy or asthmatic attack. These substances, including histamine and the leukotrienes, may also promote the inflammatory response and edema formation. 

Consistent with the notion that xenobiotic enzymes and transporters are also involved in the biotransformation and homeostasis of many endogenous chemicals, accumulating evidence has also pointed to a role of PXR in normal physiology and diseases. 

In addition to mechanical and thermal stimulation, there are a number of endogenous chemicals that activate or sensitize primary afferents. These include K+, serotonin, bradykinin, histamine, prostaglandins, leukotrienes, and neurokinins such as substance P. 

At the cellular level, plant secondary metabolites have five major effects on herbivores (a) alteration of DNA replication, RNA transcription, and protein synthesis (b) alteration of membrane transport processes (c) enzyme inhibition and activation (d) blocking of receptor sites for endogenous chemical transmitters and (e) affecting the conformation of other macromolecules (Robinson, 1979). 

They are not, therefore, endogenous chemicals produced by the activity of the organism s genes or regulated by its metabolism. It could be then concluded that the pyrroiizidine alkaloids sequestered and accumulated in these cases are needed along with other nutrients, and therefore they function as a source of vitality and metabolic activity for these organisms. Future studies should strive to further elucidate this enduring secret of alkaloids. 

Other than adenosine, there are several peptides which induce sleep (e.g., delta sleep inducing peptide). Together with endogenous chemicals interacting with the GABA benzodiazepine receptor site (e.g., (3-carbolines) identified in... 

Apply the same reasoning to this as to the level (concentration) of any other substance in the blood -be it a drug or an endogenous chemical. An unchanging plasma creatinine means, if volume of distribution is unchanged, that input equals loss from the plasma into the urine. Creatinine comes from creatine released continuously from our muscles. In old age muscle mass is less, and the input of creatine... 

E. J. Barrantes (1979). Endogenous chemical receptors some physical aspects. Anna. Rev. Biophys. Bioeng. 8 287-321. 

The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals... 

Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6-4. Presynaptic regulation by a variety of endogenous chemicals probably occurs in all nerve fibers. 

The harmful effects of a large number of foreign and endogenous chemicals involves their conversion to semiquinones (QH /Q ) This entails either the one-electron reduction of a quinone (Q) or the one-electron oxidation of a hydroquinone (QH2/QH ). Alternatively, they can arise via comproportiona-tion ... 

A number of endogenous chemicals provide effective barriers in innate immunity. They include hydrolytic enzymes of saliva, low pH of stomach and vagina and proteolytic enzymes in the small intestine. Additional examples include cryp-tidins, a-defensins, (3-defensins, interferons (IFNs), and surfactant proteins A and D. Cryptidins and a-defensins are produced in the small intestine and p-defensins are produced by the skin and respiratory tract. 

Investigation into the chemical composition of citrus has led to the isolation and identification of hundreds of individual compounds. As work has continued, biochemical, nutritional and organoleptic studies have made great strides in determining which compounds are paramount in the final determination of fruit and fruit product quality. For the purpose of this discussion, we will concern ourselves with only those quality aspects affected by endogenous chemical composition and consideration of physical or descriptive parameters will be omitted. 

Histamine is an endogenous chemical that is involved in the normal regulation of certain physiologic functions (gastric secretion, CNS neural modulation), as well as various hypersensitivity (allergic)... 

There are instances in which toxicants have chemical or structural similarities to endogenous chemicals that rely on these special transport mechanisms for normal physiological uptake and can thus utilize the same system for membrane transport. Useful examples of drugs known to be transported by this mechanism include levodopa, which is used in treating Parkinson s disease, and fluorouracil, a cytotoxic drug. Levodopa is taken up by the carrier that normally transports phenylalanine, and fluorouracil is transported by the system that carries the natural pyrimidines, thymine, and uracil. Iron is absorbed by a specific carrier in the mucosal cells of the jejunum, and calcium by a vitamin D-dependent carrier system. Lead may be more quickly moved by a transport system that is normally involved in the uptake of calcium. 

Lipophilic materials require intracellular carrier proteins to be optimally mobilized, just as they required transport proteins in the blood (Figure 10.3). Several intracellular carrier proteins that mobilize specific endogenous chemical have been characterized, although less is known of which proteins typically mobilize xenobiotics. Some of the cytosolic glutathione S-transferase proteins have been shown to noncatalytically bind xenobiotics and to be coordinately induced along with xenobiotic biotransformation enzymes and efflux transporters, suggesting that these proteins may function to mobilize xenobiotics. 

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