NAT1 (N-acetyltransferase 1 (arylamine N-acetyltransferase))

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Gene Section
Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1)
39
Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
NAT1 (N-acetyltransferase 1 (arylamine N-
acetyltransferase))
Jhon D Ruiz, José AG Agúndez, Carmen Martínez, Elena García-Martín
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain (JDR),
Department of Biochemistry & Molecular biology & Genetics, School of Biological Sciences, Badajoz,
Spain (JAGA), Department of Biochemistry & Molecular biology & Genetics, School of Biological
Sciences, Badajoz, Spain (CM, EGM)
Published in Atlas Database: February 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/NAT1ID41497ch8p22.html
DOI: 10.4267/2042/44659
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: AAC1; MNAT
HGNC (Hugo): NAT1
Location: 8p22
Picture adapted from an original prepared by Genetics Home
Reference; February 2009.
DNA/RNA
Note
In humans NAT1 is located in the NAT cluster that
comprises 230 kb and includes two functional genes,
NAT1 and NAT2. In other species the number of NAT
genes range from 0 to 4.
Transcription
The human NAT1 gene has nine exons. The coding
region is located in exon 9 and spans 870 bp. Diverse
NAT1 transcripts have been reported and two
promoters exist. The first promoter, designated as P1 is
located in the 5' flanking region of exon 1 and controls
two major (a1 and a2) transcripts. The second promoter
is located upstream of exon 4 and give rise to at least
five (b1 to b5) different transcripts. The different
transcripts appear to have different translational
efficiencies, although the biological significance of this
is unknown (revised in Butcher et al., 2007).
Pseudogene
In humans the NAT locus has a pseudogene designated
as NATP.
Protein
Note
NAT enzymes have been identified in several
vertebrate and microorganism species, whereas NAT
deficiency in the domestic and wild dog is due to
complete absence of NAT genes.
Description
The amino-terminal domain (residues 1-83) consists of
five helices and one short beta-strand. The second
domain comprises residues 85-192 and consists of nine
beta-strands and two short helices. The third domain
has a final helix which precedes the carboxy terminal
region.
Expression
NAT1 activity is expressed in liver and in many
extrahepatic tissues. The transcripts originated from the
first promoter, NATa, are expressed in kidney, liver,
lung and trachea. However the most common
transcripts are those designated as type b in the

NAT1 (N-acetyltransferase 1 (arylamine N-acetyltransferase)) Ruiz JD, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1)
40
Structure of the human NAT1 gene and common NAT1 transcripts.
Figure above and have been detected in all tissues
examinated.
Localisation
Arylamine N-acetyltransferases are cytosolic enzymes.
Function
NAT1 is a phase II enzyme that participates in the
metabolism of numerous primary arylamines and
hydrazine drugs and carcinogens. In addition to their
N-acetylation catalytic activity, NAT enzymes have
also O-acetylation activity towards N-
hydroxyarylamines.
Homology
NAT1 and NAT2 share 87% nucleotide homology in
the coding region, whereas NAT1 and NAT2 proteins
share 81% amino-acid sequence identity.
Mutations
Note
In humans NAT1 is highly polymorphic. Several
polymorphisms, most of which are single nucleotide
polymorphisms and at least 26 different haplotypes
have been described. The Figure below shows the
positions of NAT1 polymorphisms, taking as a
reference the start site in the open
reading frame (ORF) in exon 9. Nonsynonymous
polymorphisms are labeled in red font. The association
of different haplotypes with phenotypes is summarized
in the following link:
http://louisville.edu/medschool/pharmacology/Human.
NAT1.pdf.
Implicated in
Lung cancer
Note
Two independent studies have observed a significant
association of the NAT1 polymorphism with lung
cancer risk (Bouchardy et al., 1998; Wikman et al.,
2001). However these studies should be interpreted
cautiously because these do not agree on the NAT1 risk
genotype. Another study identified an increased risk
among carriers of NAT1 plus NAT2 slow genotypes
(Gemignani et al., 2007). In a meta-analysis carried out
with smokers that suffered from non small-cell lung
cancer a relevant association of the NAT1 rapid
acetylation genotype was identified (Zienolddiny et al.,
2008). Although negative associations have been
reported (Perera et al., 2006), NAT1 is emerging as the
NAT gene most likely related to lung cancer (McKay et
al, 2008).

NAT1 (N-acetyltransferase 1 (arylamine N-acetyltransferase)) Ruiz JD, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(1)
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Head and neck cancer
Note
Since chemical compounds present in tobacco are
inactivated by phase II enzymes, it has been proposed
that head and neck cancer risk could be modified by
NAT genotypes. Head and neck cancers are strongly
associated with smoking, and a few studies have
explored the role of NAT1 polymorphisms in the risk
of developing head and neck cancer in smokers.
However overall findings are inconsistent and
associations if present are weak, and indicate either a
decreased risk in carriers of the variant NAT1*10
(McKay et al., 2008), an increased risk (Katoh et al.,
1998) or a lack of association (Fronhoffs et al., 2001;
Henning et al., 1999; Agúndez, 2008).
Breast cancer
Note
The NAT1*10 variant allele was associated to
increased breast cancer risk among women who
consumed well-done meat, although the statistical
significance of this finding is low (Krajinovic et al.,
2001). Several studies, however, indicate that no major
association of NAT polymorphisms and breast cancer
risk exists (Agúndez, 2008).
Colorectal cancer
Note
A biologically plausible mechanistic hypothesis
suggest that rapid NAT1 and/or NAT2 acetylators
should more activate heterocyclic amine carcinogens
within the colon to their ultimate carcinogenic forms,
thereby predisposing them to colorectal cancer.
However sufficient evidence is available to rule out a
relevant association of NAT genotypes alone with
colorectal cancer risk. This evidence is based in nearly
thirty studies failed to detect a statistically significant
association for NAT1 genotypes both with colorectal
cancer or adenomas. In addition meta-analyses (Chen et
al., 2005; Ye et al., 2002; Houlston et al., 2001)
consistently confirm a lack of a relevant association of
NAT1 rapid acetylator genotypes and colorectal cancer
risk (revised in Agúndez, 2008).
Bladder cancer
Note
No significant association of the NAT1 genotype with
bladder cancer risk has been observed in a recent meta-
analysis, although the authors found a joint effect of
NAT1 rapid genotypes, slow NAT2 genotypes and
smoking as factors increasing cancer risk (Sanderson et
al., 2007). Overall findings are negative (Okkels et al.,
1997), although a significant risk has been described in
smokers (Taylor et al., 1998; Hsieh et al., 1999;
Cascorbi et al., 2001) and a nearly significant
association was observed in individuals exposed to
benzidine (Carreon et al., 2006).
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This article should be referenced as such:
Ruiz JD, Agúndez JAG, Martínez C, García-Martín E. NAT1
(N-acetyltransferase 1 (arylamine N-acetyltransferase)). Atlas
Genet Cytogenet Oncol Haematol. 2010; 14(1):39-43.