Aromatic amines metabolic conversion

In addition to the reversibility of the N-oxidation of certain aromatic amines, as demonstrated by in vitro metabolism studies, several irreversible detoxification mechanisms also occur. The formation of C-hydroxylated metabolites is the major route for detoxification of aromatic amines. The influence of enzyme inducers and inhibitors on the extent of C-hydroxylation of aromatic amines has been explored by several investigators (Table VII). In the case of AAF, the 1-, 3-, 5-, and 7-hydroxy derivatives were found to be formed in vivo. It was also shown in vitro that 1- and 3-hydroxy-AAF could be formed by an isomerization of V-OH-AAF. The conversion of V-OH-AAF to these hydroxy derivatives as catalyzed by various liver preparations is illustrated in Fig. 3. The effects of different species and substrates on this transformation are listed in Table VIII. Further oxidation of these o-aminophenols in vitro by mitochondria to quinonimines, which have been shown to bind to cellular protein, has been studied (Table IX). 

In retrospect, the development and standardization of S-9 has centered around a limited number of chemical types, i.e., iV-nitrosamines, aromatic amines, and polycyclics. Accordingly, the ability of microbial systems supplemented with S-9 to detect these chemicals has been rather consistent. However, the converse also appears true chemicals, other than those types with which the testing has been standardized, that are metabolized in vivo to their active forms are not as consistently detected in such in vitro testing. While further discussion of this point is reserved for later, suffice it here to note that, in general, poorly activated types include azonaphthol dyes carbamyl and thiocarbamyl compounds phenyls polyhalogenated aromatics, cyclics, and aliphatics benzodioxoles and symmetrical hydrazines. 

PAHs and aromatic amines are carcinogenic and are rapidly converted in the liver into a suite of metabolites. Considering that the point of metabolism is to alter the solubility of the compound such that it can be excreted, it stands to reason that detoxification would not only decrease the lipid solubility of the PAH but also decrease its reactivity, or in other words, its propensity to form DNA adducts. However sensible that may seem, the converse is actually true. Highly reactive metabolites, such as epoxides and quinones, are often formed during Phase I metabolism. These chemicals actually increase, rather than decrease, chemical reactivity. Consequendy, as many PAHs are metabolized and prepared for excretion, their carcinogenicity may actually increase. 

Several mechanisms may contribute to the association of meat with colon cancer. The heterocyclic amines and polycyclic aromatic hydrocarbons present in cooked meat are metabolized, in the body, to mutagens that may condense with DNA to form adducts. If the adduct occurs at a vital base, and if the adduct is not promptly repaired, cancer may result. Another possible mechanism is related to the enhanced excretion of bile salts into the intestines that occurs with a high-fat diet. In brief, the increased amount of bile salts (with a high-fat diet) that reaches the large intestines is metabolized by the gut microflora to an increased amount of modified bile salts. Specifically, lithocholic acid and deoxycholic acid are formed. These modified bile salts are thought to contribute to the conversion of a normal gut cell to a cancer cell. Recent studies suggest that chronic exposure of gut cells to these modified bile salts may result in chronic activation of protein kinase C and chronic... 

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