Amine, metabolic activation

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

There is much evidence to suggest that carcinogenic N-nitros-amines are metabolised by an oxidative process to produce an alkylating agent (J f2) One potential metabolite is therefore the corresponding N-nitrosamide resulting from 2-electron oxidation at the oc-carbon atom, and, indeed, such compounds appear to induce tumours at the site of application without metabolic activation (3) It follows that the chemical properties of N-nitrosamides are relevant to the etiology of cancer ... 

PGH synthase and the related enzyme lipoxygenase occupy a position at the interface of peroxidase chemistry and free radical chemistry and can clearly trigger metabolic activation by both mechanisms. The peroxidase pathway activates compounds such as diethylstilbestrol and aromatic amines whereas the free radical pathway activates polycyclic hydrocarbons (59). Both pathways require synthesis of hydroperoxide in order to trigger oxidation. 

Beland, F.A. and Kadlubar, F.F. (1990). Metabolic activation and DNA adducts of aromatic amines and nitroaromatic hydrocarbons. In Chemical Carcinogenesis and Mutagenesis, Cooper, C.S. and Grover, P.L. (eds), p. 267. Springer Verlag, Secaucus... 

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). 

Triphenyl amine was not mutagenic in bacterial assays with or without metabolic activation. ... 

Arylnitrenium ions are considered to be key intermediates in carcinogenic DNA damage by metabolically activated amines. The enzymatic activation of amines and the propogation of DNA-amine adducts into mutations and cellular transformations is beyond the specific scope of this chapter. Presented here is an outline of the key mechanistic issues relevant to the interaction of DNA components with various arylnitrenium ions. 

Like other aromatic amines 4-chloro-ort/20-toluidine has been shown to undergo metabolic activation resulting in covalent binding to tissue proteins, DNA and RNA both in vivo and in vitro (Hill et al., 1979 Bentley et al., 1986a,b Bimer Neumann, 1988). 

Chloro-ort/70-toluidine undergoes extensive metabolism in rodents in vivo. Like other aromatic amines, it undergoes metabolic activation via initial formation of the 7V-hydroxy derivative. The further metabolic processing of this metabolite has not been investigated. 

Like other aromatic amines, 5-chloro-ori/20-toluidine undergoes an initial metabolic activation step, probably A-oxidation, to form a nitrosoarene that can bind covalently to haemoglobin. 

As a result of a high index of clinical suspicion and, on occasion, supporting biochemical data from other investigations, one of the first specialist investigations to ascertain whether a patient has an inborn error of biogenic amine metabolism is, as mentioned above, analysis of the CSF concentrations of HVA and 5HIAA. This is often performed in conjunction with the measurement of 3-methyldopa (3-MD), also known as 3-methoxytyrosine. 3-MD is formed from L-dopa via COMT activity and accumulates in conditions where aromatic amino acid decarboxylase activity is impaired. The chemical structures of HVA, 5HIAA and 3-MD are shown in Fig. 6.2.1. 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

The enzyme found in the liver will deaminate secondary and tertiary aliphatic amines as well as primary amines, although the latter are the preferred substrates and are deaminated faster. Secondary and tertiary amines are preferentially dealky la ted to primary amines. For aromatic amines, such as benzylamine, electron-withdrawing substituents on the ring will increase the reaction rate. The product of the reaction is an aldehyde (Fig. 4.30). Amines such as amphetamine are not substrates, seemingly due to the presence of a methyl group on the a-carbon atom (Fig. 4.27). Monoamine oxidase is important in the metabolic activation and subsequent toxicity of allylamine (Fig. 4.31), which is highly toxic to the heart. The presence of the amine oxidase in heart tissue allows metabolism to the toxic metabolite, allyl aldehyde (Fig. 4.31). Another example is the metabolism of MPTP to a toxic metabolite by monoamine oxidase in the central nervous system, which is discussed in more detail in chapter 7. 

Thus, sulfate conjugation and acetylation may be involved in the metabolic activation of N-hydroxy aromatic amines, glutathione conjugation may be important in the nephrotoxicity of compounds, methylation in metal toxicity, glucuronidation in the carcinogenicity of p-naphthylamine and 3, 2 -dimethyl-4-aminobiphenyl. 

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