Foreign compound toxicity

Combs JGF, Combs SB. 1987. Selenium effect on drug and foreign compound toxicity. Pharmacol Ther 33 303-315. 

The kidney is an important organ for the excretion of toxic materials and their metaboHtes, and measurement of these substances in urine may provide a convenient basis for monitoring the exposure of an individual to the parent compound in his or her immediate environment. The Hver has as one of its functions the metaboHsm of foreign compounds some pathways result in detoxification and others in metaboHc activation. Also, the Hver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the Hver (bile) and kidney (urine) as routes of excretion, the lung may act as a route of elimination for volatile compounds. The excretion of materials in sweat, hair, and nails is usually insignificant. 

Smith, M. T., Thor, H., and Orrenius, S. (1983). The role of lipid peroxidation in the toxicity of foreign compounds to liver cells, Biochem. Pharmacol., 32, 763-764. 

For example, it is to be noted that UDP-glucuronic acid which is formed in the tissues, is used not only for polysaccharide synthesis, but also for neutralization and removal of toxic and useless materials or foreign compounds from the organism. 

Gillette, J.R. 1994. Commentary. Perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmacol. 23, 2785. 

In mammals the cytochrome P-U50 mediated monooxygenase or mixed function oxidase system involved in the elimination of lipophilic environmental contaminants and other foreign compounds, has been implicated in the carcinogen activation process. There are several distinct variants of cytochrome P-U50 in mammalian tissues and there may be more than one form of this ubiquitous cytochrome also in fish. The significance of this lies in the fact that different forms of cytochrome P-U50 result in different metabolite patterns, which in turn may reflect on the carcinogenicity or toxicity of compounds being metabolized. 

The gastrointestinal flora may modify foreign compounds and either render them toxic to their host or assist in detoxication. An example of the former is cycasin, a compound in food made from cycad nuts that by itself is not toxic to rats. Hydrolysis by the rat s microflora generates metabolites, one of which is toxic. Germ-free rats suffer no toxic effects from ingested cycasin. 

The complex Interactions of terpenes with insect growth and reproduction and with the Insects ability to metabolise potentially toxic, lipophilic foreign compounds will be discussed briefly in the following. 

Mixed Function Oxidases Oxidizing enzymes which are involved in die metabolism of many foreign compounds giving products of different toxicity front the parent compound. 

Thus, any foreign compound, which comes into contact with a biological system, will cause certain perturbations in that system. These biological responses, such as the inhibition of enzymes and interaction with receptors, macromolecules, or organelles, may not necessarily be toxicologically relevant. This point is particularly important when assessing in vitro data, and it involves the concept of a dose threshold or the lack of such a threshold, in the "one molecule, one hit" theory of toxicity. 

The distribution of a foreign compound and its rate of entry determine the concentration at a particular site and the number and types of cells exposed. The plasma concentration depends on many factors, not least of which is the metabolic activity of the particular organism. This metabolism may be a major factor in determining toxicity, as the compound may be more or less toxic than its metabolites. 

The excretion of a foreign substance can also be a major factor in its toxicity and a determinant of the plasma and tissue levels. All these considerations are modified by species differences, genetic effects, and other factors. The response of the organism to the toxic insult is influenced by similar factors. The route of administration of a foreign compound may determine whether the effect is systemic or local. 

Although there are several sites of first contact between a foreign compound and a biological system, the absorption phase (and also distribution and excretion) necessarily involves the passage across cell membranes whichever site is involved. Therefore, it is important first to consider membrane structure and transport in order to understand the absorption of toxic compounds. 

This is probably the most important mechanism of transport for foreign and toxic compounds. It does not show substrate specificity but relies on diffusion through the lipid bilayer. Passive diffusion requires certain conditions ... 

Many foreign substances are ingested orally, either in the diet or as drugs, and poisonous substances taken either accidentally or intentionally. Most suicidal poisonings involve oral intake of the toxic agent. Consequently, the gastrointestinal tract is a very important site and perhaps the major route of absorption for foreign compounds. 

Apart from influencing the absorption of foreign compounds, the environment of the gastrointestinal tract may also affect the compound itself, making it more or less toxic. For example, gut bacteria may enzymically alter the compound, and the pH of the tract may affect its chemical structure. 

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