The Pharmacogenomics Journal (2002) 2, 3042

2002 Nature Publishing Group All rights reserved 1470-269X/02 $25.00

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REVIEW

Pharmacogenetics of the arylamine

N-acetyltransferases
NJ Butcher1,2
S Boukouvala3
E Sim3
RF Minchin1,2
1

Laboratory for Cancer Medicine, Western

Australian Institute for Medical Research, Royal
Perth Hospital, Perth, Western Australia;
2
Department of Pharmacology, University of
Western Australia, Nedlands, Western
Australia; 3Department of Pharmacology,
University of Oxford, Oxford, UK
Correspondence:
Dr NJ Butcher, Laboratory for Cancer
Medicine, Level 6, Medical Research
Foundation Building, Royal Perth Hospital,
Perth, Western Australia 6000
Tel: +61 8 9224 0338
Fax: +61 8 9224 0322
E-mail: nbutcherreceptor.pharm.uwa.
edu.au

Received: 6 June 2001

Revised: 4 September 2001
Accepted: 7 September 2001

ABSTRACT

The arylamine N-acetyltransferases (NATs) are involved in the metabolism of

a variety of different compounds that we are exposed to on a daily basis.
Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified
by NATs and eliminated from the body or bioactivated to metabolites that
have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different
types of cancers. As a result, the levels of NATs in the body have important
consequences with regard to an individuals susceptibility to certain druginduced toxicities and cancers. This review focuses on recent advances in the
molecular genetics of the human NATs.
The Pharmacogenomics Journal (2002) 2, 3042. DOI: 10.1038/sj/tpj/
6500053
Keywords: N-acetyltransferase; NAT; acetylation; arylamine; polymorphism

Introduction
The arylamine N-acetyltransferases (NATs) are found in nearly all species from
bacteria to humans. They catalyse the acetyltransfer from acetylcoenzyme A to
an aromatic amine, heterocyclic amine or hydrazine compound. In humans,
acetylation is a major route of biotransformation for many arylamine and hydrazine drugs, as well as for a number of known carcinogens present in the diet,
cigarette smoke and the environment.14 The reaction pathway is catalysed by
two cytoplasmic acetyltransferases (NAT; EC 2.3.1.5), N-acetyltransferase Type I
(NAT1) and N-acetyltransferase Type II (NAT2). The genes encoding both proteins were first isolated in 1989 by Grant et al who showed that each consists
of an intronless open reading frame of 870 base pairs.5 The two genes are 87%
homologous and are located at 8p22,68 a chromosomal region commonly
deleted in human cancers.913 Ohsako and Deguchi isolated the transcript for
each gene from a human liver cDNA library in 1990.14 Sequencing of NAT1 and
NAT2 revealed a number of allelic variants that affect activity of both genes in
vivo. This work provided a genetic understanding for the long known functional
polymorphism in NAT2 activity15 and, more recently, in NAT1 activity.1618 Genetic variation modulates the acetylator status of individuals and therefore may
impact upon their predisposition to toxicity and disease. This review focuses on
the genomics of the arylamine N-acetyltransferases and the impact of genetic
variation of the enzymes on drug response in humans.
THE ARYLAMINE N-ACETYLTRANSFERASE GENE FAMILY
To date, 22 NAT-like genes have been identified in 14 different prokaryotic and
eukaryotic species, although it is likely that additional genes will be discovered
as more genomes become sequenced. The genes invariably have an intronless
coding sequence that encodes for a protein between 254 and 332 amino acids

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31

in length (Figure 1). Figure 1 shows a multiple sequence

alignment for 22 NAT proteins. The highest conserved
regions occur at the amino terminus, whereas the carboxyl
terminus shows very little conservation between species.
Consistent with the recently published crystal structure for
the Salmonella typhimurium NAT,19 all NATs possess a conserved cysteine, histidine and aspartate that have been
implicated to form a catalytic triad. Inhibitor studies20 and
site-directed mutagenesis studies21 have confirmed that the
cysteine (Cys68 in the human proteins) is crucial for NAT
activity.
A phylogenetic tree for the NAT proteins is shown in
Figure 2. It indicates the separate clustering of the prokaryotic and eukaryotic sequences, with the exception of A. mediterranei NAT which is distant from both groups. This
enzyme is part of the rifamycin B synthesis pathway and
catalyses the final amide bond formation reaction.22 The
NAT1 and NAT2 sequences for rat, mouse and hamster cluster together suggesting that the two proteins are encoded by
genes that were present before the divergence of the three
rodent species. By contrast, the two human proteins are
more closely related to each other, perhaps because the
genes duplicated later in evolution. The general relationship
of the amino acid sequences is similar to that recently published for a limited number of NAT nucleotide sequences.23

STRUCTURAL CHARACTERISTICS OF THE NAT

PROTEINS
The first crystal structure of an arylamine N-acetyltransferase
was recently published.19 Although the NAT was of bacterial
origin, it revealed a number of surprising features that provided novel structural and functional information about the
enzyme.19 Specifically, a cysteine-histidine-aspartate catalytic triad was identified in the N-terminus of the protein.
Based on structural analysis, the protein has been divided
into three domains. The first consists of a helical bundle,
located from amino acid 1 to approximately 90 (based on
numbering in Figure 1), which forms one side of a cleft in
which the cysteine involved in acetyl transfer resides. All
NATs are highly homologous in this region. The second
domain consists of residues from approximately 90 to 210
and is located on the other side of the cleft. It mostly consists of -sheet structures. The last domain at the carboxyl
terminus is a combination of -sheets and -helices, and
this region shows the greatest diversity between species. The
structural features surrounding the triad are similar to the
cysteine protease superfamily of proteins which includes the
transglutaminases, cathepsins and caspases. While these
proteins traditionally catalyse the hydrolysis of amide substrates, the NATs and the transglutaminases catalyse an acyltransfer that results in amide bond formation. This is also
the case for the NAT homolog found in A. mediterranei.22 To
date, the crystal structure of the human NATs has not been
resolved although the homology with NAT from bacteria
suggests similar features will be present.

N-ACETYLTRANSFERASE NOMENCLATURE
The first attempt to devise a consensus nomenclature for the
NATs was published in 1995 and included genes from six
species and a total of 39 alleles.15 Since then, many new
alleles have been identified and the nomenclature for these
was updated in 2000.24 The Human Gene Nomenclature
Committee has agreed that the symbol NAT be assigned to
the arylamine N-acetyltransferase genes. Currently, NAT
also is used for unrelated genes such as yeast protein N-terminal acetyltransferase, human noradrenalin transporter,
eukaryotic translation initiation factor, translation repressor
protein and death associated protein 5.
The classification of the eukaryotic genes into NAT1 and
NAT2 subfamilies has been done largely on a historical basis
of the research area and is a consensus nomenclature.24
While this has been appropriate for most members of the
genes for NAT, it has raised some confusion with the mouse,
hamster and rat Nat2 genes, which encode for proteins with
substrate specificity similar to human NAT1 (acetylate paminobenzoic acid;2528). At this stage, mouse is the only
species to have three genes for NAT, pseudogenes excepted.
Classification of different alleles into different clusters is
based on the most significant nucleotide substitution
present.24
The prokaryotic genes are sufficiently dissimilar to the
eukaryotic genes for NAT to preclude subclassification.
Consequently, the prokaryotic genes are referred to as Nat
only. An international committee has been established to
oversee the nomenclature of the N-acetyltransferases. The
committee is responsible for nomenclature updates and
assignment of new alleles. This has been found to be essential to ensure consistence of allelic names in the literature.
A Web site that provides information about the naming of
existing and new alleles for all species can be found at
http://www.louisville.edu/medschool/pharmacology/NAT.
html.
REACTION MECHANISM AND SUBSTRATE
SPECIFICITY
The arylamine N-acetyltransferases differ from the many
other acetyl coenzyme A-dependent transferases present in
cells because of their ping-pong bi bi reaction mechanism.29,30 The reaction takes place in two separate steps.
Initially, acetyl coenzyme A binds to the enzyme and the
acetyl moiety is transferred from the cofactor to a cysteine
(Cys68 for the human isoforms) of the protein. Coenzyme A
is then released. The second step involves the binding of
substrate to the acetylated enzyme following which the acetyl moiety is transferred to the substrate. Finally, the acetylated product is released from the enzyme. The first step of
the reaction can proceed in the absence of arylamine substrate.31 It may be that the enzyme exists in an acetylated
state in the cell when no substrate is present, although this
has not been shown to date, and the stability of the acetylated intermediate should be assessed.
There is no clear structural motif that determines substrate
specificity for the different isoforms of NAT. In general, paminobenzoic acid (PABA), p-aminobenzoyl glutamate and

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Figure 1 ClustalX multiple sequence alignment of 22 NAT proteins from 14 different species. A conservation score for each column is shown by the histogram. The shaded
columns represent the catalytic triad which is conserved in all NATs. The three domains, identied from the crystal structure of NAT from S. typhimurium, are shown as
shaded bars below the histogram.

Pharmacogenetics of the arylamine N-acetyltransferases

32
NJ Butcher et al

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NAT activity has been reported although there is no evidence of a NAT-like gene in their genome. The very high Km
values reported for substrates like PABA and 2-aminofluorene indicate that the acetylation reaction is very inefficient
and is probably catalysed by a protein unrelated to the
NATs.34
One prokaryotic NAT homolog deserves further attention.
The Rif gene cluster in A. mediterranei that encodes the proteins necessary for the synthesis of rifamycin B includes the
gene RifF for rifamycin amide synthase. The amino acid
similarity of RifF to the other prokaryotic NATs is approximately 45% (Figure 1) and the enzyme possesses the conserved catalytic triad in its amine terminus. RifF catalyses an
amide bond formation during the latter stages of rifamycin
synthesis (Figure 3).22 Other NAT-like proteins may become
evident as more genomes are sequenced and it is possible
that the NAT protein has evolved in different species to
undertake quite different cellular tasks.32

Figure 2 Phylogenetic tree for the NATs determined from the

amino acid alignments shown in Figure 1. The dendrogram shows
the relative distance between each sequence on the horizontal axis.
All sequences were acquired from GenBank including the chicken
NATX (accession number J03737) which, to date, has not been
assigned a name.

p-aminosalicylic acid (PAS) are considered specific substrates

for human NAT1 (or mouse NAT2). These substrates can be
characterised by the presence of relatively small hydrophilic
substitutions in the para position of the aromatic ring. By
contrast, sulfamethazine, procainamide and dapsone are
acetylated primarily by human NAT2. Some compounds
such as 2-aminofluorene are excellent substrates for both
human NAT1 and NAT2.3
The prokaryotic NATs acetylate PABA poorly or not at all
and their range of substrates, which includes isoniazid, suggests that they are functionally similar to the human NAT2
isoform.32 However, the prokaryotic NATs are also capable
of acetylating the human NAT1 specific substrate 5-aminosalicylic acid,33 indicating that prokaryotic NATs should not
be considered functionally equivalent to either NAT1 or
NAT2 in humans. In some bacterial strains such as H. pylori,

GENE LOCALISATION, STRUCTURE AND EXPRESSION

Two NAT isoenzymes have been identified in humans,
namely NAT1 and NAT2, which are the products of distinct
genetic loci, designated NAT1 and NAT2, respectively.6 A
related pseudogene, NATP1, has also been identified,6 which
contains multiple frameshift and nonsense mutations. The
two functional NAT genes share an 87% nucleotide identity,
which translates to an 81% homology at the amino acid
level. While the entire transcript of NAT1 is derived from a
single exon, that of NAT2 is derived from the protein encoding exon together with a second noncoding exon of 100 bp
located about 8 kb upstream of the translation start site.6,35
Human NAT1 and NAT2, as well as NATP1, have been localised to the short arm of chromosome 8,6,36 more specifically
in region 8p22.8 The NAT loci are separated by only 170
360 kb and are in the orientation NAT1 NATP1 NAT2,
with NAT1 being on the centromeric side of marker D8S261
and NAT2 coinciding with marker D8S21.36 Both NAT1 and
NAT2 genes display pronounced allelic variation, with 26
different human NAT1 and 29 different human NAT2 alleles
identified to date.24
A similar situation is present in the mouse where three
functional genes, designated Nat1, Nat2 and Nat3, have

Figure 3 RifF, an NAT-like protein from Amycolatopsis mediterranei,

catalyses an amide bond formation during the latter stages of rifamycin synthesis.22 Although RifF is similar to the other prokaryotic
NATs, it has evolved to function specically in the synthesis of rifamycin B.

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34

been identified to encode for NAT isoenzymes.37,38 Mouse

NAT2 shows similar substrate specificity with human NAT1,
while mouse NAT1 is capable of metabolising the human
NAT2-specific substrate isoniazid.39 To date, no specific substrate has been identified for NAT3, although the encoding
locus appears to be functional.38,40 The localisation and genomic organisation of the mouse Nat genes is similar to their
human counterparts. The three genes are clustered together
in a 130-kb genomic region on mouse chromosome 8, cytogenetic band B3.1-B3.341 and within a genetic distance of
about 31 cM from the centromere.42 This chromosomal
region is syntenic with the region harbouring the genes for
human NAT on chromosome 8p. Polymorphism has been
detected only in the Nat2 gene of both A/J37 and A/HeJ43
inbred mice, in the form of a missense A T mutation at
position 296 of the open reading frame, causing the slow
acetylator phenotype. It is of interest that mouse Nat2 also
possesses a short non-coding exon, located about 6 kb
upstream of the intronless open reading frame.41 This raises
the possibility that mouse Nat2 may be the genetic
orthologue of the human NAT2 gene, although mouse
NAT2 and human NAT1 proteins appear to be functionally equivalent.
Information about the localisation and genomic organisation of the Nat genes in other eukaryotic species has been
limited. All genes have an intronless open reading frame and
polymorphism in NAT activity has been described in strains
of rabbits,44 hamsters45 and rats,46 all of which possess two
Nat genes. Upstream non-coding exons have also been
described for the rabbit Nat genes.47 Cats and other felids
only have one gene for NAT,48 while dogs lack NAT activity,
due to absence of Nat genes in their genome.49
HUMAN NATs
Human NAT2 Alleles
Since the human NAT2 locus was established as the site of
the classical acetylation polymorphism,50,51 the study of
NAT2 allelic variation has been an area of intense investigation. To date, 29 different NAT2 alleles have been detected
in human populations (Table 1; reviewed in 15,24,52). Each of
the variant alleles is comprised of between one and four
nucleotide substitutions, of which 13 have been identified,
located in the protein encoding region of the gene. Nine of
these lead to a change in the encoded amino acid (C190T,
G191A, T341C, A434C, G499A, G590A, A803G, A845C, and G857A),
while the remaining four are silent (T111C, C282T, C481T,
and C759T).
Several studies have been performed that show clear correlations between NAT2 genotype and phenotype.5355 Early
genotyping studies screened for the presence of the C481T
(M1), the G590A (M2), the G857A (M3) and sometimes the
G191A (M4) nucleotide changes, all of which were shown to
cause a slow acetylation phenotype. Moreover, there was a
gene-dosage effect. Individuals who were homozygous for
NAT2 polymorphisms had a slow acetylator phenotype,
individuals heterozygous for NAT2 polymorphisms had an
intermediate acetylator phenotype, and individuals who
lacked NAT2 polymorphisms had a rapid acetylator pheno-

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Table 1 Human NAT2 alleles (adapted from References

and 56)
Allele

Phenotype

Nucleotide
change(s)

NAT2*4
NAT2*5A
NAT2*5B

Rapid
Slow
Slow

None
T341C, C481T
T341C, C481T, A803G

NAT2*5C

Slow

T341C, A803G

NAT2*5D
NAT2*5E

Slow
Slow

T341C
T341C, G590A

NAT2*5F

Slow

NAT2*6A
NAT2*6B
NAT2*6C

Slow
Slow
Slow

T341C, C481T, T759T,

A803G
C282T, G590A
G590A
C282T, G590A, A803G

NAT2*6D
NAT2*7A
NAT2*7B
NAT2*10
NAT2*11
NAT2*12A
NAT2*12B
NAT2*12C
NAT2*13
NAT2*14A
NAT2*14B
NAT2*14C

Slow
Slow
Slow
Unknown
Unknown
Rapid
Rapid
Rapid
Rapid
Slow
Slow
Slow

T111C, C282T, G590A

G857A
C282T, G857A
G499A
C481T
A803G
C282T, A803G
C481T, A803G
C282T
G191A
G191A, C282T
G191A, T341C, C481T,
A803G

NAT2*14D

Slow

G191A, C282T, G590A

NAT2*14E

Slow

G191A, A803G

NAT2*14F

Slow

G191A, T341C, A803G

NAT2*14G

Slow

G191A, C282T, A803G

NAT2*17
NAT2*18
NAT2*19

Slow
A434C
Unknown A845C
Slow
C190T

52

Amino acid
change(s)
None
Ile114 Thr
Ile114 Thr,
Lys268 Arg
Ile114 Thr,
Lys268 Arg
Ile114 Thr
Ile114 Thr,
Arg197 Gln
Ile114 Thr,
Lys268 Arg
Arg197 Gln
Arg197 Gln
Arg197 Gln,
Lys268 Arg
Arg197 Gln
Lys286 Glu
Lys286 Glu
Glu167 Lys
None
Lys268 Arg
Lys268 Arg
Lys268 Arg
None
Arg64 Gln
Arg64 Gln
Arg64 Gln,
Ile114 Thr,
Lys268 Arg
Arg64 Gln,
Arg197 Gln
Arg64 Gln,
Lys268 Arg
Arg64 Gln,
Arg114 Thr,
Lys268 Arg
Arg64 Gln,
Lys268 Arg
Gln145 Pro
Lys282 Thr
Arg64 Trp

type. It should be noted that the method of detection of the

above polymorphisms only identifies a subset of the variant
alleles found in human populations, and there is potential
for the misclassification of genotype and deduced phenotypes (reviewed in 56).
Initial studies in liver tissue suggested that the slow acetylator phenotype associated with the presence of certain
nucleotide substitutions in the protein encoding region of
the NAT2 gene was due to a marked decrease in NAT2 protein content, while NAT2 mRNA levels remained
unchanged.57 Several studies have since investigated the
mechanism by which nucleotide substitutions in the NAT2
gene affect acetylation capacity by the use of recombinant

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35

expression systems.5862 Hein and coworkers63 performed a

comprehensive study that assessed the acetylation capacity
of 16 different NAT2 alleles in a bacterial expression system.
Of the seven specific NAT2 substitutions that they examined, the T341C, G590A, G857A, and G191A substitutions produced recombinant NAT2 allozymes with reduced acetylation capacities, while the C481T, C282T, and A803G
substitutions produced recombinant NAT2 allozymes with
acetylation capacities similar to the wild-type NAT2 4 protein. As a result, NAT2 alleles that contain any of the specific
substitutions that produced recombinant NAT2 allozymes
with reduced acetylation capacities are associated with a
slow acetylator phenotype, and include the NAT2 5, NAT2
6, NAT2 7, NAT2 14, and NAT2 17 clusters (see Table 1).
The molecular mechanisms responsible for the production of the slow acetylator phenotypes are not well
understood at present. Some base changes appeared to cause
a slow acetylation phenotype by producing an unstable protein. NAT2 allozymes encoded by alleles with base substitutions at positions 191, 590, or 857 were found to be significantly more unstable in bacterial expression systems
than the wild-type protein.52,61,64 However, in these studies
the amount of immunodetectable NAT2 protein was not different upon expression of the variant and wild-type alleles.
This is in contrast to the earlier observations by Grant and
coworkers57 who showed that liver NAT2 content was markedly reduced in slow acetylators, suggesting that the artificial environment of bacterial expression systems may not
accurately reflect what occurs in mammalian cells with
regard to protein degradation.
Recently, a study by Leff and coworkers62 characterised
several different human NAT2 alleles in a yeast expression
system. They found that three novel alleles, namely NAT2*
5D (T341C), NAT2*14G (G191A, C282T, and A803G), and
NAT2*6D (C111T, C282T, and G590A), expressed proteins that
had N- and O-acetylation capacities similar to the expressed
protein of the commonly occurring slow NAT2*5B allele,
and significantly less than that of the wild-type NAT2*4
allele. The expression of NAT2 5B and NAT2 5D was found
to be significantly lower than that of the wild-type protein,
suggesting that the base substitution at position 341, which
is common to the NAT2*5 cluster, is sufficient for reduction
in NAT2 protein expression. This was not found to be the
case for NAT2 6D and NAT2 14G, which were expressed at
levels comparable to wild-type. By contrast, NAT2 6D and
NAT2 14G were found to be significantly less stable than
wild-type.
The frequency of the slow acetylator phenotype varies
considerably among ethnic groups,65 and this is due to the
differing frequencies of the polymorphisms that correspond
to the slow acetylator alleles. In Caucasian and African
populations, the frequency of the slow acetylation phenotype varies between 40 and 70%, while that of Asian populations, such as Japanese, Chinese, Korean, and Thai, range
from 10 to 30% (reviewed in 66). Caucasian and African
populations have high frequencies of NAT2*5 alleles
(28%) and low frequencies of NAT2*7 alleles (5%), while
Asian populations have low incidences of NAT2*5 alleles

(7%) and higher incidences of NAT2*7 alleles (10%).

Also, NAT2*14 alleles are almost absent from Caucasian and
Asian populations (1%), but are present in African populations at comparably higher frequencies (8%).
Human NAT1 Alleles
Historically, NAT1 was thought to be genetically invariant
or monomorphic in nature. However, wide inter-individual
variability in NAT1 activity towards PABA or PAS51,6772 was
suggestive of a genetic polymorphism, but NAT1 activities
were generally unimodally distributed. It wasnt until 1993
when Vatsis and Weber73 first reported the existence of several allelic variations at the NAT1 locus that interest in the
NAT1 gene was aroused, marking the beginning of a systematic survey of NAT1 genotypes. To date, 26 different NAT1
alleles have been detected in human populations (Table 2;
reviewed in 15,24,52), however, only a small number have
been shown to alter phenotype in vivo. Hughes and coworkers17 used PAS as a probe drug to phenotype a population
for NAT1 activity. By measuring urinary metabolite ratios,
they were able to detect individuals with marked impairments of NAT1 function. However, there was only a moderate correlation between phenotypes determined by in vivo
and in vitro methods, and the authors themselves suggest
that less than 50% of the phenotypic variation observed in
vivo was related to variation in NAT1 function. It appears
that the measurement of NAT1 activity of blood cells is the
most reliable method of phenotyping for NAT1. While little
is known about the relative expression of NAT1 in various
human tissues, studies in the rabbit model suggest that
NAT1 activity is comparable in most tissues, including blood
cells.17 Therefore, it is reasonable to assume that NAT1
activity of blood cells is a good surrogate of systemic activity
in humans.
The first report of a correlation between NAT1 genotype
and phenotype was by Bell and coworkers in 1995.74 They
showed that the NAT1*10 allele was associated with activity
two-fold higher than that of the wild-type allele, NAT1*4,
in bladder and colon tissue samples.74 In the bladder, higher
levels of DNA adducts were detected in NAT1*10 heterozygotes compared with NAT1*4 homozygotes.75,76 The
NAT1*10 allele also has been associated with a marginally
elevated activity in liver samples4 and erythrocytes.77 NAT1*
10 has no mutations in the protein encoding region of the
gene, but contains two nucleotide substitutions (T1088A
and C1095A) in its 3-untranslated region. The T1088A base
change alters the consensus polyadenylation signal
(AATAAA AAAAAA) leading to the suggestion that
increased activity may be due to enhanced mRNA stability.74,78 However, several recent studies,1618,79,80 do not
support the idea that the NAT1*10 allele is associated with
elevated NAT1 activity. As a result, the functional significance of this allele remains unclear at present.
A population study16 showed a distribution of NAT1
activity that was clearly bimodal in nature, with 8% of the
individuals being slow acetylators. Moreover, the above
study was one of the first to report a correlation between
NAT1 genotype and phenotype involving the slow acetyl-

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Table 2 Human NAT1 alleles (adapted from References

and 56)
Allele

Phenotype Nucleotide change(s)

NAT1*4
NAT1*3
NAT1*5

Normal
Normal
Normal

NAT1*10
NAT1*11A

Rapid?
Normal

NAT1*11B

Normal

NAT1*11C

Normal

NAT1*14A

Slow

NAT1*14B
NAT1*15
NAT1*16

Slow
Slow
Slow

NAT1*17
NAT1*18A

Slow
Unknown

NAT1*18B
NAT1*19
NAT1*20
NAT1*21
NAT1*22
NAT1*23
NAT1*24
NAT1*25
NAT1*26A

Unknown
Slow
Unknown
Rapid
Slow
Unknown
Rapid
Rapid
Unknown

NAT1*26B

Unknown

None
C1095A
G350,351C, G497
499
C, A884G,
976, 1105
T1088A, C1095A
C344T, A40T,
G445A, G459A,
T640G, 9(10651090),
C1095A
C344T, A40T,
G445A, G459A,
T640G, 9(10651090)
C344T, A40T,
G459A, T640G,
T640G, 9(10651090)
G560A, T1088A,
C1095A
G560A
C559A
AAA insertion
after1091, C1095A
C190T
3(10641087), T1088A,
C1095A
3(10641087)
C97T
T402C
A613G
A752T
T777C
G781A
A787G
TAA insertion(1066
1091)
, C1095A
TAA insertion(1066

52

Amino acid
change(s)
None
None
Arg117 Thr,
Arg166 Thr,
Glu167 Gln
None
Val149 Ile,
Ser214 Ala
Val149 Ile,
Ser214 Ala

Arg187 Gln
Arg187 Gln
Arg187 Stop
None
Arg64 Trp
None
None
Arg33 Stop
None
Met205 Val
Asp251 Val
None
Glu261 Lys
Ile263 Val
None
None

1091)

NAT1*27
NAT1*28
NAT1*29

Unknown T21G, T777C

Unknown TAATAA
deletion(10851090)
Unknown T1088A, C1095A,
1025

None
None
None

ator alleles NAT1*14 and NAT1*17. Individuals that were

heterozygous for either polymorphism had approximately
half the activity of individuals that lacked these base
changes. Furthermore, Western blots for NAT1 showed that
low activity was due to a parallel decrease in NAT1 protein
content, indicating that slow acetylator status was a result
of a decrease in the amount of a functionally normal
enzyme rather that the presence of a protein with altered
acetylation capacity. A later study also found a correlation
between NAT1 phenotype and the low activity NAT1*14
allele,79 with heterozygote carriers of the allele having about
50% of the activity of noncarriers. Bruhn and coworkers79

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also found that individuals who possessed a NAT1*11 allele

had slightly lower activities compared with individuals who
were homozygous for NAT1*4, NAT1*10, or NAT1*3, all of
which had similar activities. Interestingly, the same study
identified an individual who was homozygous for the
NAT1*15 allele and who had no measurable NAT1 activity.
The NAT1*15 allele contains a base substitution (C559T) in
the protein encoding region of the NAT1 gene that introduces a stop codon, leading to the production of a truncated, inactive protein.17 Hughes and coworkers17 also identified an individual who possessed two low activity alleles,
namely NAT1*14B/NAT1*15, and who subsequently had
very low acetylation capacity. As with several NAT2 low
activity alleles, there appears to be a gene-dosage effect for
the low activity NAT1 alleles, with heterozygotes having
about half the activity of NAT1*4 wild-type individuals, and
homozygotes (or compound heterozygotes) for low activity
alleles having little or no NAT1 activity. The exception is a
NAT1*14A/NAT1*14B heterozygote identified by Payton
and Sim,77 whose activity was less than the NAT1*4 homozygotes but was still detectable. The frequency of slow acetylator alleles for NAT1 is low. The most common low
activity allele, NAT1*14, has been identified in Caucasian
populations ranging from 1.3 to 3.7%.1618,79,81,82 Interestingly, a much higher frequency of the NAT1*14 allele (25%)
was reported for a Lebanese population.83 Since no homozygous individuals were identified in the above study, 50%
of the Lebanese population had a slow acetylator genotype.
This indicates that NAT1, like NAT2, shows considerable
interethnic variability.
Some of the more common variant NAT1 alleles have
been characterised in bacterial and/or mammalian
expression systems. Recombinant expression of NAT1*14 in
a bacterial system by Hughes and coworkers17 showed that
the variant protein had a 15- to 20-fold decrease in affinity
for the substrate PAS and showed a 4-fold decrease in Vmax
compared with recombinant NAT1 4 wild-type protein. The
same study also showed that expression of NAT1*15 in E.coli
produced a truncated protein that was totally inactive.
Therefore, NAT1*14 (A and B) and NAT1*15 are low activity
alleles, which is consistent with phenotyping studies using
human blood cells.16,79,81 Two other low activity alleles,
NAT1*17 and NAT1*22, have been expressed in bacterial
systems and both produced variant proteins that had no
detectable NAT1 activity towards PAS.18 Also, in the same
study, immunoreactive NAT1 17 and NAT1 22 protein levels
were markedly decreased compared with wild-type NAT1 4
protein levels. NAT1*19 was classified as a nonfunctional
allele because the base substitution (C97T) introduces a
premature stop codon.18
The effects of coding and 3-noncoding polymorphisms
in the NAT1*11 allele were characterised by de Leon and
coworkers80 recently. Using recombinant expression of
NAT1*11 in both bacterial and mammalian systems, they
showed that no major differences existed in catalytic or
other properties of the NAT1 11 protein compared with
wild-type NAT1 4 protein. This is in agreement with an earlier study,17 which showed that the activity of recombinant

Pharmacogenetics of the arylamine N-acetyltransferases

NJ Butcher et al

37

NAT1 4 and NAT1 11 were similar, but is in contrast to

another study which reported a slightly reduced activity of
blood cells from individuals who carried the NAT1*11
allele.79 de Leon and coworkers,80 using a mammalian
expression system, have recently shown that the NAT1*16
phenotype is caused by polymorphism in the 3-untranslated region that leads to a decrease in protein expression.
NAT1*16 has a triple adenosine insertion on the 3 side of
the polyadenylation signal (AATAAA) which significantly
alters the secondary structure of the pre-mRNA, leading to
a 2-fold reduction in the amount of NAT1 16 protein and
activity, compared with NAT1 4 and NAT1 10.
Some NAT1 alleles also may produce proteins with activities that are higher than that of the wild-type protein NAT1
4. Recombinant expression of NAT1*21, NAT1*24, and
NAT1*25 in bacterial systems produced allozymes with
activities 2- to 3-fold higher than NAT1 4.18 However, the
levels of immunoreactive protein expressed by NAT1*4,
NAT1*21, NAT1*24, and NAT1*25 were equivalent.18 The
functional significance of the other NAT1 variants remains
unclear at present.
NAT AND DISEASE
The association between acetylator status and the risk of
various diseases has been extensively reported, and reviewed
in detail.8487 Altered risk with either the slow or rapid
phenotype has been observed for bladder, colon and breast
cancer, systemic lupus erythematosis, diabetes, Gilberts disease, Parkinsons disease and Alzheimers disease. These
associations imply a role for environmental factors that are
metabolised by the NATs, in particular NAT2, in each disorder. However, identifying those factors has remained elusive. Humans are exposed to many toxic NAT substrates
including the food-derived heterocyclics present in the diet
as well as arylamines such as 4-aminobiphenyl and -naphthylamine present in tobacco smoke.8891 Moreover, occupational exposure to arylamine carcinogens such as benzidine has also been reported.92,93
Because of the role of acetylation in the metabolic activation and detoxification of arylamine and heterocyclic carcinogens, acetylator status and cancer risk has been widely
investigated. Unlike the relatively rare but highly penetrant
genes involved in familial cancers, those genes responsible
for metabolic polymorphisms have low penetrance and
cause only a moderate increase in cancer risk. Nevertheless,
their widespread occurrence in the general population suggests they are a significant contributor to individual risk. In
1979, Lower et al94 first demonstrated an association
between the slow acetylator phenotype and bladder cancer.
This work was followed by many independent studies. However, few diseases have consistently demonstrated a relationship between phenotype and risk. For example, several studies have implicated the rapid phenotype as an increased risk
factor for colon cancer,9597 whereas others have been
unable to confirm this finding.98100 Geographical differences, ethnicity, lack of study power, dietary differences and
differences in other risk factors between study groups have
been suggested as reasons for variable results from inde-

pendent laboratories. Recent reports suggesting that NAT

activity may be altered by environmental factors and substrate-dependent down-regulation101 may also explain why
inconsistent associations have been seen.
When acetylator phenotype has been linked to carcinogen exposure, more consistent results have been reported.
For example, the rapid phenotype has emerged as a strong
risk factor for colorectal cancer in those individuals who
have a higher exposure to the food-derived heterocyclic
amines.99,100,102 These observations provide strong circumstantial evidence that the heterocyclic amines have an
important role in colorectal cancer, and extensive animal
studies support this.103106 They also illustrate the importance of establishing associations between genetic polymorphisms and disease risk. From such studies, it should be
possible to pursue the causative agent(s) of the disease where
no obvious candidate agent is evident.
Recently, the NAT2 acetylator phenotype has been linked
to increased risk associated with neurodegenerative diseases
such as Parkinsons disease and Alzheimers disease.107109
For late-onset Alzheimers disease, an odds ratio of 3.0 (95%
CI 1.37.3) has been reported for the rapid phenotype in
non-apoE epsilon carriers.109 By contrast, the slow phenotype appears to increase risk of Parkinsons disease with an
odds ratio of 3.58 (95% CI 1.966.56).107 Although these
results need to be confirmed with larger epidemiological
studies, they point to environmental factors that are substrates for the NATs having a role in the onset of these diseases. Alternatively, the different alleles for NAT2 that produce the rapid or slow phenotype may co-segregate with
unrelated genes that are the causative agent for the different
neurodegenerative diseases.
NAT and Drug Response
The genetic polymorphism in N-acetyltransferase activity
was first discovered in patients treated with isoniazid for
tuberculosis.110 This drug is primarily excreted following
acetylation catalysed by NAT2. Since then, many therapeutic agents have been shown to be polymorphically acetylated in humans. These include hydralazine, procainamide, sulphamethazine, endralazine, a number of
sulphonamides, nitrazepam and dapsone. However, the
incidence of failed or less effective clinical response as a
consequence of acetylation polyphorphism is uncommon.
This is because most drugs that are metabolised by the NATs
have a wide therapeutic window or because acetylation is a
minor metabolic pathway. An exception is hydralazine.
Early studies showed that the antihypertensive activity of
hydralazine was less in rapid acetylators and that a 40%
higher dose was necessary for a similar therapeutic effect
compared with slow acetylators.111 This difference appeared
to be due to a change in the bioavailability of the drug
which decreased from 33% in slow acetylators to less than
10% in rapid acetylators.112
A more common consequence of the polymorphic acetylation of therapeutic agents is an increase in the frequency
and severity of side-effects associated with either the rapid
or slow phenotype (Table 3). These adverse effects often

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NJ Butcher et al

38

Table 3 Effect of acetylator status on drug response and

toxicity
Drug
Dapsone
Sulphamethoxazole
Hydralazine

Phenotype

Effect

Reference

Slow
Slow
Slow

Neurotoxicity
Hypersensitivity
Systemic lupus
erythematosus
Decreased therapeutic
effect
Interaction with phenytoin
Interaction with rifampicin
Various adverse reactions
Various toxicities
Hepatotoxicity
Nausea/vomiting
Leukopenia
Systemic lupus
erythematosus
Decreased therapeutic
effect
Contact dermatitis

118,126

Rapid
Isoniazid

Amonafide
Procainamide

Slow
Slow
Slow
Slow
Slow
Slow
Rapid
Slow

Phenelzine

Rapid

p-Phenylenediamine

Slow

Cotrimoxazole
Sulphasalazine

127,128
129,130

111,112

131
132
133
114
134
135
120,121
136138

139,140

141

arise as the result of a shift in the metabolic pathways

responsible for the activation and detoxification of the drug.
This is best illustrated by the amine-containing sulphonamides, such as sulphamethoxazole, that undergo hydroxylation to a reactive N-hydroxy metabolite capable of covalently binding to macromolecules and giving rise to
idiosyncratic adverse reactions.113 These drugs can also be
acetylated by NAT2 to non-reactive N-acetyl metabolites. In
slow acetylators, a higher proportion of the drug is Nhydroxylated and consequently, these individuals are at a
greater risk of sulphonamide-induced toxicity.114116 However, as pointed out by Spielberg, the incidence of severe
adverse side effects to sulphonamides is much less than the
incidence of the slow acetylator phenotype suggesting that
other factors predispose individuals to idiosyncratic
adverse reactions.113
Risk of developing side effects, such as neurotoxicity or
haemolytic anemia, to dapsone therapy is very similar to
that described for the sulphonamides.117 The most severe
incidence of toxicity occurred in individuals with a slow acetylator phenotype who are rapid hydroxylators, which is
consistent with the role each pathway has in the activation
and detoxification of the drug.118
While slow acetylators are at a greater risk of toxicity from
sulphonamides and dapsone, other therapeutic agents exhibit increased incidence of adverse reactions in rapid acetylators. Amonafide is a novel arylamine that has previously
been used in clinical trials for the treatment of various cancers. It undergoes N-acetylation to an active metabolite that
contributes to systemic toxicity. Several studies have shown
that myelosuppression is greater in rapid acetylators (white
blood cell nadirs of 500 l1) compared to slow acetylators
(white blood cell nadirs of 3400 l1) following a standard
dose of 300 mg m2 daily for 5 days.119121. This has led to
different recommended doses for the two groups.120,122

The Pharmacogenomics Journal

The recent discovery and cloning of prokaryotic NATs has

raised the possibility that bacterial metabolism of drugs and
other xenobiotics can contribute to their therapeutic and
toxicological efficacy in vivo.33,123 Payton and associates
showed that M. smegmatis transformed with the M. tuberculosis NAT gene has a 3-fold higher resistance to isoniazid due
to an increase in acetylation of the drug.123 These observations suggested that the level of NAT expression in target
bacteria may be an important therapeutic modifier for antibiotics that are extensively acetylated. In addition, polymorphisms in the bacterial NAT genes could lead to different
therapeutic responses.
Okumura et al124 found that the acetylated metabolites of
a range of arylamines such as p-aminobenzoic acid, 4-aminobiphenyl and 1-aminopyrene were excreted in the urine
and feces of dogs that lack N-acetyltransferase activity.49
They showed that the intestinal microflora were responsible
for the formation of the acetyl derivatives. Similarly, the
microflora in the intestine of rats contribute to the acetylation of 2-nitrofluorene and the formation of DNA adducts
in liver, kidney, lung and heart following oral administration.125 Taken together, these studies suggest that bacterial NAT has a role in the activation and detoxification of
xenobiotics in the host organism and may play an
important role in the metabolism of anti-inflammatory
drugs, such as 5-aminosalicylic acid.33
CONCLUDING REMARKS
Although considerable allelic variation exists for both NAT1
and NAT2, our understanding of the molecular mechanisms
and functional significance of many of these alleles, particularly for NAT1, is still limited. The majority of functional
studies to date have been performed in bacterial expression
systems, and the results of such studies may not necessarily
accurately reflect what occurs in vivo, due to differences in
degradation/processing pathways between bacterial and
mammalian systems. Discrepancies between the two systems have been reported with regard to NAT protein content
and slow acetylator alleles, and characterisation using mammalian systems may provide a better understanding of the
molecular mechanisms leading to different NAT phenotypes.
Much of the research in the area of NATs has involved
identifying relationships between allele frequencies and disease, particularly different forms of cancers. Although several studies have reported associations between different
NAT alleles and various cancers, other studies have failed to
do so. While these inconsistencies may be due to several
factors, such as differences in exposure to arylamine carcinogens, it may well be that genotype does not necessarily accurately reflect phenotype. For example, although the regulation of NAT1 expression certainly has a genetic
component, this only accounts for part of the observed
variability in NAT1 activities. We have shown that significant variation in NAT1 activity can be observed within a
single phenotype and within the same individuals measured
on different occasions, suggesting that a considerable part
of the variation in activity is environmentally based. In sup-

Pharmacogenetics of the arylamine N-acetyltransferases

NJ Butcher et al

39

port of this, we have recently provided evidence for substrate-dependent regulation of NAT1,101 and identified a
minimum promoter sequence for the human NAT1 that
consists of an AP-1-like motif flanked on either side by a
TCATT sequence (manuscript in preparation). Transient
transfection assays showed that both the AP-1 motif and the
3-TCATT sequence were essential for basal promoter
activity, while the 5-TCATT sequence appeared to act as an
attenuator of phorbol 12-myristate 13-acetate induction.
Moreover, antibody supershift assays suggested that c-jun,
Oct-1, and YY1 transcription factors form complexes with
the NAT1 minimum promoter. Therefore, environmental
factors that alter the expression of transcription factors, such
as those mentioned above also may modulate the basal
expression of NAT1 in vivo. There also is the possibility that
other promoter sequences and binding motifs exist further
upstream from the minimum basal promoter sequence that
could modulate NAT1 activity under certain conditions.
DUALITY OF INTEREST

12

13

14

15

16

17

18

19

None declared.
20

ABBREVIATIONS
NAT1
NAT2
PAS
PABA

arylamine N-acetyltransferase 1
arylamine N-acetyltranferase 2
p-aminosalicylic acid
p-aminobenzoic acid

21

22
23

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