Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
105
N-Acetyltransferase
N-Acetyltransferase (NAT) catalyzes acetylation of a diverse variety of aromatic
amine drugs and carcinogens (Evans and White 1964). Interindividual difference
in drug acetylation is one of the earliest examples of pharmacogenetic variation.
Acetylation of many drugs, such as procainamide and isoniazid, exhibits bimodal
distribution among individuals, with two distinct phenotypes as rapid and slow
acetylators. Slow acetylators are at increased susceptibility to isoniazid- and
hydralazine-associated toxicity and to certain cancers due to exposure to industrial
chemicals such as α- and β-naphthylamine and benzidine. Individuals with a poor
acetylator phenotype have an increased risk of developing lung, bladder, and gastric
cancers if exposed to carcinogenic arylamines for a long period of time. The phenotypes
of acetylation are attributed to differences in the enzymatic activities of NAT.
There are two arylamine acetyltransferase isozymes in humans: type I (NAT1)
and type II (NAT2). Although these two isozymes share greater than 93% of their
290 amino acids, they have overlapping but different substrates. NAT2 catalyzes
acetylation of hydralazine, isoniazid, and procainamide, while NAT1 catalyzes
p-aminosalicylate. The NAT2 isozyme functions to both activate and deactivate
arylamine and hydrazine drugs and carcinogens. Polymorphisms in NAT2 are also
associated with higher incidences of cancer and drug toxicity. They also show distinct
expression patterns, with NAT2 expressed mainly in the liver and gut, and
NAT1 in many adult tissues as well as in early embryos.
NAT1 and NAT2 are encoded by two genes located on chromosome 8p22, a region
often deleted in cancers. The two genes are separated by 870 bp and there is pseudogene
(NATP) located in between. Polymorphisms in both genes are responsible for the
N-acetylation polymorphisms. Most alleles of NAT1 and NAT2 are haplotypes of several
point mutations with one signature mutation causing reduced enzymatic activity.
These alleles usually cause unstable protein or affect the activity of the protein. A full
description of NAT1 and NAT2 alleles can be found at http://nat.mbg.duth.gr/ although
it was initially curated and hosted at the website of University of Louisville.
There are 15 NAT2 alleles identified in humans, and NAT2*5A, NAT2*6A, and
NAT2*7A are associated with the slow acetylator phenotypes (Fretland et al. 2001;
Zang et al. 2007). There are great differences of frequency of NAT2 alleles across
ethnic groups. The slow acetylation form is present in up to 90% of some Arab populations,
40–60% of whites, and only to 25% of East Asians.
There are 26 NAT1 alleles (Hein et al. 2000). Interestingly, amino acid change
at position 64 from arginine to tryptophan substitution (W64D) is found both in
NAT1*17 and NAT2*19. This missense mutation results in an unfolded protein
accumulating intracellularly, which is degraded through the ubiquitination pathway.
Another interesting allele of NAT1 is the NAT1*10 allele with no amino acid
change in the coding region. The NAT1*10 allele has deletions and insertions at
the 3′-untranslated region (3′-UTR). It has been reported that the NAT1*10 allele
is associated with increased activity in colon cancer (Bell et al. 1995; Zenser et al.
1996). However, the biological effect of this allele is still uncertain because it seems
to have no correlation between the copy number of NAT1*10 allele and the level of
NAT1 activity.