Amines reactive metabolites

Another drug that is associated with a relatively high incidence of both drug-de-pendent and autoimmune antibodies is diclofenac [38], In some cases the specificity of the diclofenac-induced autoantibodies is very similar to that induced by a-methyldopa [39], Diclofenac is a secondary aromatic amine and is oxidized to reactive metabolites by both cytochromes P450 and myeloperoxidase [40], When patient sera were tested, it was addition of the 4-hydroxy metabolite that most commonly led to agglutination of red cells [41] this metabolite has the potential to be air oxidized to a reactive iminoquinone. 

Most reactive metabolites produced by CYP metabolic activation are electrophilic in nature, which means that they can react easily with the nucleophiles present in the protein side chains. Several functional groups are recurrent structural features in M Bis. These groups have been reviewed by Fontana et al. [26] and can be summarized as follows terminal (co or co — 1) acetylenes, olefins, furans and thiophenes, epoxides, dichloro- and trichloroethylenes, secondary amines, benzodioxoles (methylenediox-yphenyl, MDP), conjugated structures, hydrazines, isothiocyanates, thioamides, dithiocarbamates and, in general, Michael acceptors (Scheme 11.1). 

Adapted from Cheever et al. (1980) Son et al. (1980) KuUcami et al. (1983) and Gupta et al. (1987) Brackets indicate postulated proximate or reactive metabolites of ort/zo-toluidine, based on data from the metabolism of other aromatic amines. 

Figure 13.10. NAT-mediated metabolic activation of heterocyclic aromatic amines. 2-AF is not a NAT substrate for A-aectylation (compare with 2-NA, 4-ABP A-acetylation in Figure 13.9). 2-AF is detoxified by P4502B1 ring hydroxylation. 2-AF is also metabolized via P4501A2-mediated A-hydroxylation. The resultant A-hydroxy 2-AF is a good substrate of conjugation reactions by NATs as well as by UGTs and SULTs and is converted to reactive metabolites for DNA adduct formation.

There is speculation that long-term exposure to cyclic tertiary amines such as cocaine, phencyclidine, and phenothiazines may result in biochemical lesions through the formation of reactive metabolites. This premise is supported by the induction of a parkinsonian state by MPTP. Although the initial product of microsomal oxidation is an electrophilic endocyclic iminium intermediate which is thought to be the reactive species primarily responsible for neurotoxicity, there is now evidence that the iminium is in equilibrium with the endocyclic enamine and that the latter is transformed to reactive species. The presence of iminium- detoxifying enzymes in cytosolic and microsomal fractions suggests that rapid inactivation of the iminium... 

MetaDrug also includes 89 rules to predict likely reactive metabolites such as quinones, aromatic and hydroxyl amines, acyl glucuronides, acyl halides, epoxides, thiophenes, furans, phenoxyl radicals, phenols, and aniline radicals. Molecules with reactive groups are marked and highlighted. 

Penrose 1978). More recent studies have shown that Mytilus edulis has the capacity to metabolize PAHs and aromatic amines (Marsh et al. 1992) in addition to its ability to metabolize benzo[a]pyrene in the absence of NADH or NADPH cofactors (Lemaire et al. 1993). It has also been demonstrated that a Mytilus sp. can form reactive metabolites of benzo[a]pyrene that attach to DNA (Marsh et al. 1992). 

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. 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

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