Metabolism of foreign substances

Some other examples of selective alteration will now be given. Whereas vertebrates convert phenols to j8-glucuronides, most insects form phenyl-)8-glucosides instead. In a patient whose normal lung tissue converted 1-naphthol to 1-naphthyl sulfate, squamous carcinoma tissue made 1-naphthyl glucu-ronide from the same phenol (see Section 3.5, p. 87 for the biochemistry of these alternative routes) (Cohen, Gibby and Mehta, 1981). 

The amino acid tryptophan is degraded by the higher plants to indolyl-3-acetic acid which is an important growth hormone for them, whereas bacteria usually degrade it to tryptamine, and mammals to 3-hydroxyanthranilic acid and thence to nicotinic acid which is an indispensable metabolite. 

The most selective known poison for mammals is norbormide 4.90) a rat-killer. It is 5-(o -hydroxy-Q -2-pyridylbenzyl)-7-(a-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide. Only the genus Rattus is affected, and death follows its powerful and irritant local vasoconstrictor action this leads to ischaemia of most of the vital organs which then cease to function. It is non-lethal to over 30 species of other mammals (including mice and other rodents), birds, and fish. It is suggested that all animals other than rats can detoxify norbormide (Roszkowski, 1965). Norbormide has not proved very successful in rat extermination because the vermin soon recognize its odour and learn to avoid it. 

For further reading on the selective metabolism of foreign substance, see Williams (1959), Jakoby (1980), Jakoby, Bend and Caldwell (1982), and the Journal Xenobiotica, 

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Reduction Phase I can also be accomplished by means of reductions. The reductive enzymes are localized both in the micro-somes and the cytosol. They trigger the enzymatic transformation of ketones, aldehydes, sulphoxides, nitro- and azo-linkages, etc. The intestinal flora also contributes to the reductive metabolism of foreign substances. 

Tab. 3.18 Variable and non-variable factors influencing the biochemical mechanisms involved in the metabolism of foreign substances...

Alcohol plays an important role in the metabolism of foreign substances and is responsible for numerous interactions with drugs. A special type of cytochrome P 450 (P 450 II E 1) is induced by the chronic intake of alcohol. This subtype may influence other drug-metabolizing enzyme systems and possibly account for the carcinogenicity of dimethylnitrosamine in the gastrointestinal tract. 

Metabolization of foreign substances Sinusendothelial cells are also capable of endocytosis and, by virtue of their extensive enzyme equipment, in a perfect position to metabolize different kinds of foreign substances. They are endowed with a good stock of acid phosphatase, acid DNase, p-N-acetylglucosaminidase, P-glucu-ronidase, arylsulphatase (A, B), cholesterol esterase, col-lagenases, etc. 

For further reading on the selective metabolism of foreign substances, see Lehninger (1982) and Stryer (1981) and for plant biochemistry, see Bonner and Varner (1976). A simple account, for revising the basic facts, can be found in Campbell and Kilby (1975), and a related work in pictorial form, suitable for projection in Campbell and Smith (1982). 

The majority of chemical substances which the animal body recognises as foreign are metabolised and transformed into other substances irrespective of whether the foreign chemical is toxic or not. In the case of toxic compounds, the toxic effects may be due to the compound as administered or after its conversion within the body to a toxic substance. The metabolism of foreign substances can be regarded as one occurring in two phases [86—87]. The reactions of the first phase are those such as oxidation, reduction, or hydrolysis. Those of the second phase are synthetic reactions usually termed conjugations (Table 2.5). 

Enzymes catalysing special catabolic pathways. (Metabolism of foreign substances, e.g. drugs Exoenzymes, including snake venoms and bacterial exotoxins)... 

Side chain oxidation of alkylbenzenes is important in certain metabolic processes One way m which the body rids itself of foreign substances is by oxidation m the liver to compounds that are more polar and hence more easily excreted m the urine Toluene for example is oxidized to benzoic acid by this process and is eliminated rather readily... 

The tear film fulfills several important functions in the eye such as formation and maintenance of a smooth refracting surface over the cornea, lubrication of the eyelids, transportation of metabolic products (O2 and C02) to and from the epithelial cells and cornea, and elimination of foreign substances and bactericidal action [10,11]. 

The kidney is an important organ for the excretion of toxic materials and their metabolites, 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 liver has as one of its functions the metabolism of foreign compounds some pathways result in detoxification and others in metabolic activation. Also, the liver may serve as a route of elimination of toxic materials by excretion in bile. In addition to the liver (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. 

Compounds and their metabolites need to be removed from the body via excretion, usually through the kidneys or the feces. Unless excretion is complete, accumulation of foreign substances can affect normal metabolism adversely. 

Due to the multiplicity of substances to be eliminated, both substrate-specific and substrate-nonspecific elimination mechanisms are necessary. The liver is thus capable of eliminating a maximum number of foreign substances with little biomolecular effort. By means of its nonspecific elimination systems, the liver is generally able to cope metabolically with the daily variety of foreign substances as well as with newly formed ones. (s. tab. 3.17)... 

The cognate receptors, e.g., the PPAR and the FXR, are quite promiscuous with respect to the nature of the ligand and have been shown to be able to bind a broad range of lipophilic ligands. This type of receptors is thought to be involved in the homoostasis of metabolism and in the detoxification of foreign substances. 

In addition to its role in surfactant production, the type II cell also has a progenitor function, acting as the stem cell of the alveolar epithelium. The alveolar type I cells are highly susceptible to injury by oxygen and a variety of noxious substances. In such situations, type II cells can differentiate into type I cells and thus regenerate the gas-exchanging alveolar surface. Other functions of the type II cell are also believed to be the metabolism of foreign compounds (xenobiotic metabolism) and fluid and electrolyte absorption from the alveolar sacs into the interstitial matrix that surrounds the alveoli. 

Cytochrome P-450 hydroxylate many compounds. These include the hydroxylations of steroid hormone synthesis and the hydroxylation of thousands of xenobiotics (foreign compounds), including drugs such as phenobarbital and environmental carcinogens such as benzpyrene, a constituent of the smoke from tobacco and backyard grills. Hydroxylation of foreign substances usually increases their solubility and is a step in their detoxification, or metabolism and excretion. In some cases, however, some of these reactions activate potentially carcinogenic substances to more reactive species. Aflatoxin B, for example, is converted to a more reactive species either by hydroxylation or epoxidation. 

Most metabolic transformations of foreign substances in the body occur on the basis of catalysis by enzymes from the endoplasmatic reticulum, particularly liver cells, and only a small portion of these reactions occur in cells of the remaining tissues. Enzymes participating in the metabolic transformation of foreign substances are not commonly produced in the body and thus, the elimination and transformation of foreign substances, particularly those of a synthetic origin, is a slow process [1-4]. 

When the toxicity is manifested by a single dose of the substance, study whether pretreatments that are known to alter the rate or pattern of metabolism of foreign compounds will alter the incidence or severity of the toxicity. 

Metabolic alteration of foreign substances has often been called detoxification , but examples are known where the product of an e.r. enzyme is more... 

For further reading The metabolic alteration of foreign substances is a highly specialized topic with an enormous literature, of which the following give a modest cross-section. 

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