Acetyltransferases included in EC 231

Two acetyltransferases (ATs) have major implications in drug metabolism: N-acetyltransferases 1 and 2 (NAT-1 and NAT-2)57 (see 5.06 Principles of Drug Metabolism 2: Hydrolysis and Conjugation Reactions). Both enzymes catalyze the acetyl transfer from acetyl-CoA to amines or hydroxylamines.

Since, in contrast to most phase II reactions of drug metabolism, the metabolites of NAT reactions (typically amides) are usually less hydrophilic than their parent compounds (typically amines), the function of NAT appears to be primarily the inactivation of biologically active, potentially toxic compounds, rather than a conversion to more hydrophilic metabolites.1 The role of NATs in the detoxification of the procarcinogenic aryl amines is ambivalent but dependent on the nature of the substrate: N-acetylation of the aromatic amine is a detoxification reaction, since it competes with the formation of the hydroxylamine, i.e., with the initiation of the toxification pathway. However, if N-oxidation takes place first, the resulting hydroxylamine is also a substrate for NAT leading to the N-O-acetate ester (an acetoxyamino-group) from which acetate is easily cleaved off, which results in the generation of a reactive nitrenium ion. Thus, the balance between toxification and detoxification is in part determined by the velocity of the oxidative pathway relative to the acetylation pathway, which in turn is in part dependent on the substrate in question. In man, this leads to a high interindividual variability in risk since the expression of CYP1A2, the major contributor to the hydroxylation of aromatic amines, differs greatly among individuals, and NAT-2, which is often quantitatively very important in the acetylation of aryl amines and aryl hydroxylamines, is polymorphic. Slow acetylators are very slow in the acetylation of aromatic amines and their metabolites. The acetylator phenotype appears to be decisive for the organ selectivity of the tumor formation. Rapid acetylators are less susceptible to bladder cancer development caused by (occupational or therapeutic) aromatic amines since rapid acetylation effectively competes against the first step (hydroxylamine formation) in the major toxification pathway. Conversely, rapid acetylators have a higher risk of developing colorectal cancer. The causative agents for these colorectal cancers may be heterocyclic aryl amines arising from amino acids during high-temperature food preparation, such as PhIP. These are poor substrates for both NATs, hence oxidative formation of the corresponding hydroxylamines is favored. This makes NATs into predominately toxifying enzymes in this case. Hence, rapid acetylators are at greater risk for developing colorectal cancer from the food-derived heterocyclic amines in the gut.58

The NAT-2 polymorphism also has consequences for drug toxicities. Isoniazide, for example, has a very prolonged half-life in slow acetylators, which can lead to accumulation and toxicity. The acetylator phenotype can be assayed with caffeine as an in vivo probe.59 One strong cup of coffee is sufficient for this purpose. A ratio between the metabolites 5-acetylamino-6-amino-3-methyl uracil (AAMU) and 1-methylxanthine (1X) greater than two indicates a rapid acetylator.

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