Alternative titles; symbols
HGNC Approved Gene Symbol: NAT1
Cytogenetic location: 8p22 Genomic coordinates (GRCh38): 8:18,170,467-18,223,689 (from NCBI)
Using a rabbit cDNA for arylamine N-acetyltransferase (EC 2.3.1.5), Blum et al. (1990) cloned 3 NAT genes from human leukocyte DNA. Two of them, NAT1 (AAC1) and NAT2 (612182), were shown to be functional; the third appeared to be a pseudogene (NATP).
Using rabbit N-acetyltransferase to probe a human liver cDNA library, Ohsako and Deguchi (1990) cloned NAT1 and NAT2, which they designated D-24 and O-7, respectively. Both deduced proteins contained 290 amino acids. The calculated molecular mass for NAT1 was 33.6 kD. Northern blot analysis of human liver mRNA detected only weak expression of a 1.5-kb NAT1 transcript.
Blum et al. (1990) presented evidence that the NAT2 gene is the site of the polymorphism that was first identified through 'isoniazid inactivation' and is also known as 'acetylator phenotype.' The NAT1 gene is responsible for the N-acetylation of certain arylamine drugs such as p-aminosalicylic acid and shows no variability, i.e., is monomorphic. The rates of elimination in vivo and assimilation in vitro of p-aminosalicylic acid do not differ among rapid and slow acetylators. Vatsis et al. (1991), who confirmed that isoniazid acetylation is produced by the NAT2 locus, also demonstrated a NAT pseudogene.
By assaying lysates obtained from transfected Chinese hamster ovary (CHO) cells, Ohsako and Deguchi (1990) confirmed NAT1 had high N-acetyltransferase activity. Examination of its substrate specificity revealed that NAT1 acetylated p-aminobenzoic acid efficiently, but sulfamethazine was a poor substrate. This substrate specificity differed from that shown by NAT2.
It had been proposed that NAT1 has an endogenous role in the acetylation of the folate catabolite p-aminobenzoyl-L-glutamate (pABGlu) to produce the major urinary product, N-acetyl-pABGlu. The murine homolog of human NAT1 is concentrated in the neural tube during development. Smelt et al. (2000) showed that human NAT1 (but not NAT2) is expressed in preimplantation embryos at the blastocyst stage and also in early placenta (less than 5.5 weeks). The authors proposed that NAT1 is a candidate risk factor for susceptibility to neural tube defects.
Sim et al. (2000) presented an update on the genetics, structure, expression, and function of arylamine N-acetyltransferases in prokaryotes and eukaryotes.
Most NAT1 mRNAs originate at the P1 promoter located 11.8 kb upstream of the exon containing the open reading frame (ORF). Barker et al. (2006) characterized an alternative NAT1 promoter, P3, lying 51.5 kb upstream of the NAT1 ORF. RT-PCR confirmed ubiquitous expression from the P1 promoter, with some weakly expressed bands suggesting alternative splicing. Expression from the P3 promoter was strong in kidney, liver, lung, ovary, trachea, and fetal liver and weaker in prostate, testis, and fetal brain. Other weakly expressed transcripts were occasionally detected in other tissues. Variable expression of the P3 promoter was detected in 8 human cell lines, with highest expression in HepG2 cells. In HepG2 cells and the 4 human tissues with highest P3 expression, Barker et al. (2006) identified 102 P3 transcriptional start sites. The 2 most commonly used sites, at positions -41 and -43, fell within the context of an initiator-type promoter element, consistent with the absence of an adjacent upstream TATA box. Functional studies in HepG2 cells revealed a 435-bp minimal promoter that included an 84-bp sequence in which most of the P3 start sites were clustered.
Blum et al. (1990) mapped the NAT1 and NAT2 genes to chromosome 8pter-q11 by probing somatic cell hybrid DNA. Hickman et al. (1994) mapped both the NAT1 and NAT2 genes to chromosome 8p23.1-p21.3 by fluorescence in situ hybridization. The 2 loci were mapped to mouse chromosome 8 by Mattano et al. (1988). Matas et al. (1997) found that the genes AAC1, AAC2, and AACP (a pseudogene) are located in a region of about 2 Mb on 8p22 in the following order: tel--D8S261--AAC1--AACP--AAC2(D8S21)--cen.
The observation that chronic exposure to carcinogenic chemicals (e.g., cigarette smoke) does not inevitably lead to cancer initiated numerous studies aimed at understanding the basis for individual susceptibility. Aromatic amine carcinogens undergo host-mediated metabolic conversion to chemically active electrophiles in order to produce genotoxic lesions which initiate tumorigenesis. Doll et al. (1997) noted that the N-acetylation of aromatic amines exhibits interindividual differences in human populations. A number of epidemiologic studies suggest that genetic variation in the N-acetylation of aromatic amines may infer predisposition to various cancers related to aromatic amine carcinogens. Although genetic polymorphism for the NAT2 N-acetyltransferase has been well established on phenotypic and genetic grounds as the basis of rapid, intermediate, and slow acetylation, a genetic polymorphism for NAT1 was first discovered by Vatsis et al. (1995). Eight different human NAT1 alleles were identified: NAT1*3, -*4, -*5, -*10, -*11, -*14, -*15, and -*16. The NAT1*10 allele (108345.0001) has been associated with increased risk of colon and urinary bladder cancers and with higher levels of N-acetyltransferase activity and DNA adducts in aromatic amine tumor target organs such as colon and urinary bladder (Badawi et al., 1995; Bell et al., 1995; Bell et al., 1995). Doll et al. (1997) reported an allele they designated NAT1*17 (108345.0002), the expressed protein of which catalyzed the N-acetylation of aromatic amines and the O- and N,O-acetylation of their N-hydroxylated metabolites at rates up to 2-fold higher than wildtype recombinant human NAT1.
Bouchardy et al. (1998) evaluated the effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk in 150 lung cancer patients and 172 control individuals, all French Caucasian smokers. A significant association was observed between lung cancer and NAT1 genotypes with a gene dosage effect. Compared with homozygous rapid acetylators, the lung cancer risk was 4.0 for heterozygous rapid acetylators, 6.4 for homozygous normal acetylators, and 11.7 for heterozygous slow acetylators. None of the individuals were homozygous slow acetylators. No significant association was found between NAT2 genotype and lung cancer.
NAT1 catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens. Despite wide interindividual variability in activity, NAT1 was historically considered to be monomorphic in nature. Allelic variation at the NAT1 locus (Vatsis and Weber, 1993) suggested that it may be a polymorphically expressed enzyme. Butcher et al. (1998) found that NAT1 activity in peripheral blood mononuclear cells in 85 individuals was bimodally distributed with approximately 8% of the population being slow acetylators. Subsequent sequencing of the individuals having slow acetylator status showed all to have either a 190C-T or a 560G-A base substitution located in the protein-encoding region of the NAT1 gene. The first of the substitutions changed a highly conserved arg64, which others had shown to be essential for fully functional NAT1 protein. The 190C-T mutation had not previously been reported and was designated NAT1*17 by Butcher et al. (1998). (This is a different mutation from that designated NAT1*17 by Doll et al. (1997); see 108345.0002.) The 190C-T mutation changed a CGG (arg) codon to TGG (trp). The 560G-A mutation changed a CAA (gln) codon to GAA (glu). Butcher et al. (1998) described a novel method using linear PCR and dideoxy terminators for the detection of these variants. Neither variant was found in the rapid acetylator population. Because NAT1 can bioactivate several carcinogens, they reviewed other polymorphisms of NAT1 that had been described.
Moisio et al. (1998) analyzed polymorphisms of the NAT1 gene in 2 groups of Finnish families with hereditary nonpolyposis colorectal cancer (HNPCC) to facilitate detection of possible modifying factors. In kindreds with 'mutation 1' of the MLH1 DNA mismatch repair gene (120436)--the largest group in their study, consisting of 28 families--presence of the NAT1 allele 10 was identified as a risk factor for distal tumor location; the median age of onset was lower among NAT1 allele 10-positive individuals in both this group and the group with MLH1 'mutation 2,' which consisted of 9 families. Moisio et al. (1998) concluded that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair.
Patin et al. (2006) undertook a study to investigate the evolutionary history of the NAT region by unraveling the relative influences of natural selection and human demography in determining present day variability. They first resequenced NAT1, NAT2 (612182), and the pseudogene NATP in a multiethnic panel of 80 individuals. The 3 genes are located within 200 kb of each other, on 8p. To further investigate the global linkage disequilibrium (LD) patterns in the NAT region, they selected 21 SNPs--including 5 NAT1 and 7 NAT2 SNPs retrieved from the initial sequence-based dataset as well as 9 intergenic SNPs--to cover the entire 200-kb region. These markers were all genotyped in an extended collection of 563 individuals originating from 13 different ethnologically well-defined human populations. This combined study design allowed these workers to define a detailed map of LD of the NAT region as well as to perform a number of sequence-based neutrality tests and the long-range haplotype (LRH) test. The data demonstrated distinctive patterns of variability for the 2 genes: the reduced diversity observed at NAT1 is consistent with the action of purifying selection, whereas NAT2 functional variation contributes to high levels of diversity. In addition, the LRH test identified a particular NAT2 haplotype (NAT2*5B) under recent positive selection in Western/Central Eurasians. This haplotype harbors the mutations of 341T-C (612182.0002) and encodes the 'slowest-acetylator' NAT2 enzyme, suggesting a general selective advantage for the slow-acetylator phenotype. Of note, the NAT2*5B haplotype, which seems to have conferred a selective advantage during the past approximately 6,500 years, exhibits today the strongest association with susceptibility to bladder cancer and adverse drug reactions. On the whole, the patterns observed for NAT2 well illustrated how geographically and temporally fluctuating xenobiotic environments may have influenced not only our genome variability but also our present day susceptibility to disease.
As indicated by Evans (1998), until about 1991 interest was focused on N-acetyltransferase-2 (NAT2; 612182) because of the 'isoniazid polymorphism.' This was reviewed in detail by Evans (1993). Later in the 1990s, interest in NAT1 developed for various reasons: direct examination of the gene revealed variants, and then phenotypic performance was found to correlate with genotypes. NAT1 is much more widespread in the body than NAT2, which is confined to liver and gut. The great ability of NAT1 to detoxify by acetylation carcinogenic amines, such as those produced by grilling meat and detectable in the urine soon after consumption, further heightened interest in this form of the enzyme.
Vatsis et al. (1995) described a consolidated classification system and nomenclature for prokaryotic and eukaryotic N-acetyltransferases. In their system, the root symbol NAT was used throughout.
Hein et al. (2008) described a database maintaining a revised nomenclature and classification of NAT alleles in humans and select nonhuman mammals.
See Bell et al. (1995, 1995) and Badawi et al. (1995).
Doll et al. (1997) described a novel NAT1 allele that they designated NAT1*17. They found that it is similar to NAT1*11 except for a 445G-A nucleotide transition resulting in the amino acid substitution val149 to ile (V149I) in the NAT1 coding region. The V149I substitution yielded no significant changes in levels of immunoreactivity, as detected by Western blot, nor in intrinsic stability of the recombinant N-acetyltransferase protein. However, V149I yielded expression of recombinant NAT1 protein that catalyzed the N-acetylation of aromatic amines and the O- and N,O-acetylation of their N-hydroxylated metabolites at rates up to 2-fold higher than wildtype recombinant human NAT1.
Badawi, A. F., Hirvonen, A., Bell, D. A., Lang, N. P., Kadlubar, F. F. Role of aromatic amine acetyltransferases, NAT1 and NAT2, in carcinogen-DNA adduct formation in the human urinary bladder. Cancer Res. 55: 5230-5237, 1995. [PubMed: 7585581]
Barker, D. F., Husain, A., Neale, J. R., Martini, B. D., Zhang, X., Doll, M. A., States, J. C., Hein, D. W. Functional properties of an alternative, tissue-specific promoter for human arylamine N-acetyltransferase 1. Pharmacogenet. Genomics 16: 515-525, 2006. [PubMed: 16788383] [Full Text: https://doi.org/10.1097/01.fpc.0000215066.29342.26]
Bell, D. A., Badawi, A. F., Lang, N. P., Ilett, K. P., Kadlubar, F. F., Hirvonen, A. Polymorphism in the N-acetyltransferase 1 (NAT1) polyadenylation signal: association of NAT1*10 allele with higher N-acetylation activity in bladder and colon tissue. Cancer Res. 55: 5226-5229, 1995. [PubMed: 7585580]
Bell, D. A., Stephens, E. A., Castranio, T., Umbach, D. M., Watson, M., Deakin, M., Elder, J., Hendrickse, C., Duncan, H., Strange, R. C. Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer. Cancer Res. 55: 3537-3542, 1995. [PubMed: 7627961]
Blum, M., Grant, D. M., McBride, W., Heim, M., Meyer, U. A. Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 9: 193-203, 1990. [PubMed: 2340091] [Full Text: https://doi.org/10.1089/dna.1990.9.193]
Bouchardy, C., Mitrunen, K., Wikman, H., Husgafvel-Pursiainen, K., Dayer, P., Benhamou, S., Hirvonen, A. N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk. Pharmacogenetics 8: 291-298, 1998. [PubMed: 9731715] [Full Text: https://doi.org/10.1097/00008571-199808000-00002]
Butcher, N. J., Ilett, K. F., Minchin, R. F. Functional polymorphism of the human arylamine N-acetyltransferase type 1 gene caused by C190T and G560A mutations. Pharmacogenetics 8: 67-72, 1998. [PubMed: 9511183] [Full Text: https://doi.org/10.1097/00008571-199802000-00009]
Doll, M. A., Jiang, W., Deitz, A. C., Rustan, T. D., Hein, D. W. Identification of a novel allele at the human NAT1 acetyltransferase locus. Biochem. Biophys. Res. Commun. 233: 584-591, 1997. [PubMed: 9168895] [Full Text: https://doi.org/10.1006/bbrc.1997.6501]
Evans, D. A. P. Genetic Factors in Drug Therapy: Clinical and Molecular Pharmacogenetics. Cambridge: Cambridge Univ. Press , 1993. Pp. 211-305.
Evans, D. A. P. Personal Communication. Saudi Arabia 6/1/1998.
Hein, D. W., Boukouvala, S., Grant, D. M., Minchin, R. F., Sim, E. Changes in consensus arylamine N-acetyltransferase gene nomenclature. Pharmacogenet. Genomics 18: 367-368, 2008. [PubMed: 18334921] [Full Text: https://doi.org/10.1097/FPC.0b013e3282f60db0]
Hickman, D., Risch, A., Buckle, V., Spurr, N. K., Jeremiah, S. J., McCarthy, A., Sim, E. Chromosomal localization of human genes for arylamine N-acetyltransferase. Biochem. J. 297: 441-445, 1994. [PubMed: 8110178] [Full Text: https://doi.org/10.1042/bj2970441]
Matas, N., Thygesen, P., Stacey, M., Risch, A., Sim, E. Mapping AAC1, AAC2 and AACP, the genes for arylamine N-acetyltransferases, carcinogen metabolising enzymes on human chromosome 8p22, a region frequently deleted in tumours. Cytogenet. Cell Genet. 77: 290-295, 1997. [PubMed: 9284941] [Full Text: https://doi.org/10.1159/000134601]
Mattano, S. S., Erickson, R. P., Nesbitt, M. N., Weber, W. W. Linkage of Nat and Es-1 in the mouse and development of strains congenic for N-acetyltransferase. J. Hered. 79: 430-433, 1988. [PubMed: 3209851] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a110546]
Moisio, A.-L., Sistonen, P., Mecklin, J.-P., Jarvinen, H., Peltomaki, P. Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer. Gastroenterology 115: 1387-1394, 1998. [PubMed: 9834266] [Full Text: https://doi.org/10.1016/s0016-5085(98)70017-4]
Ohsako, S., Deguchi, T. Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. J. Biol. Chem. 265: 4630-4634, 1990. [PubMed: 1968463]
Patin, E., Barreiro, L. B., Sabeti, P. C., Austerlitz, F., Luca, F., Sajantila, A., Behar, D. M., Semino, O., Sakuntabhai, A., Guiso, N., Gicquel, B., McElreavey, K., Harding, R. M., Heyer, E., Quintana-Murci, L. Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes. Am. J. Hum. Genet. 78: 423-436, 2006. [PubMed: 16416399] [Full Text: https://doi.org/10.1086/500614]
Sim, E., Payton, M., Noble, M., Minchin, R. An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes. Hum. Molec. Genet. 9: 2435-2441, 2000. [PubMed: 11005799] [Full Text: https://doi.org/10.1093/hmg/9.16.2435]
Smelt, V. A., Upton, A., Adjaye, J., Payton, M. A., Boukouvala, S., Johnson, N., Mardon, H. J., Sim, E. Expression of arylamine N-acetyltransferases in pre-term placentas and in human pre-implantation embryos. Hum. Molec. Genet. 9: 1101-1107, 2000. [PubMed: 10767335] [Full Text: https://doi.org/10.1093/hmg/9.7.1101]
Vatsis, K. P., Martell, K. J., Weber, W. W. Diverse point mutations in the human gene for polymorphic N-acetyltransferase. Proc. Nat. Acad. Sci. 88: 6333-6337, 1991. [PubMed: 2068113] [Full Text: https://doi.org/10.1073/pnas.88.14.6333]
Vatsis, K. P., Weber, W. W. Structural heterogeneity of Caucasian N-acetyltransferase at the NAT1 gene locus. Arch. Biochem. Biophys. 301: 71-76, 1993. [PubMed: 8442668] [Full Text: https://doi.org/10.1006/abbi.1993.1116]
Vatsis, K. P., Weber, W. W., Bell, D. A., Dupret, J.-M., Price Evans, D. A., Grant, D. M., Hein, D. W., Lin, H. J., Meyer, U. A., Relling, M. V., Sim, E., Suzuki, T., Yamazoe, Y. Nomenclature for N-acetyltransferases. Pharmacogenetics 5: 1-17, 1995. [PubMed: 7773298] [Full Text: https://doi.org/10.1097/00008571-199502000-00001]