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Gene Review

NAT2  -  N-acetyltransferase 2 (arylamine N...

Homo sapiens

Synonyms: AAC2, Arylamide acetylase 2, Arylamine N-acetyltransferase 2, N-acetyltransferase type 2, NAT-2, ...
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Disease relevance of NAT2

  • While evidence from this study cannot be conclusive, our data suggest that NAT1 and NAT2 variants may explain an approximately twofold increase in polyp number in the FAP colon [1].
  • However, compared to individuals with rapid NAT2 genotype, women with the very slow acetylator genotype (NAT2*5), who smoked for 20 years showed an increased breast cancer risk (OR=2.29; 95% CI 1.06-4.95) [2].
  • We found no association with colorectal cancer risk with NAT2 genotype or any of the other polymorphic genes associated with the metabolism and disposition of heterocyclic amine carcinogens [3].
  • 3-NBA showed a 3.8-fold and 16.8-fold higher mutagenic activity in Salmonella strains expressing human NAT1 and human NAT2, respectively, than in the acetyltransferase-deficient strain, whereas N-Ac-N-OH-ABA was only clearly (but weakly) mutagenic in Salmonella DJ460 expressing human NAT2 [4].
  • We conclude that smoking increases risk of colorectal adenomas and that SULT1A1 and NAT2 only modestly modify this association [5].
  • These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk [6].
  • Analyses reveal an enhanced effect for smoking intensity and bladder cancer in NAT2 slow acetylators which increases with intensity [7].

Psychiatry related information on NAT2


High impact information on NAT2

  • The acetylation polymorphism concerns the metabolism of a variety of arylamine and hydrazine drugs, as well as carcinogens by the cytosolic N-acetyltransferase NAT2 [13].
  • RESULTS: Neither smoking nor NAT2 status was independently associated with breast cancer risk [14].
  • The GSTM1-null and the NAT2 slow-acetylator genotypes have been associated with increased risks for the development of environmentally induced cancers [15].
  • The binding site for the nodule-specific trans-acting factor, NAT2, present in the PE-A segment, was removed without affecting expression significantly [16].
  • The same factors also had a high affinity for a protein binding site from a soybean leghemoglobin gene and appeared to be closely related to the soybean nodule factor NAT2, which binds to A/T-rich sequences in the lbc3 and nodulin 23 genes [Jacobsen et al. (1990). Plant Cell 2, 85-94] [17].

Chemical compound and disease context of NAT2


Biological context of NAT2

  • NAT2 slow genotypes were also associated with CpG G:C-A:T (OR, 6.2; CI:0.7-52), whereas GSTM1 null was associated with non-CpG G:C-A:T (OR, 7.8; CI, 0.9-65) [23].
  • In conclusion, molecular genetic analysis of a large sample specified the increased bladder cancer risk of those who are deficient in NAT2 and GSTM1; the other traits proved to be of minor impact [24].
  • The same criteria established that recombinant NAT2 was indistinguishable from one of two previously observed N-acetyltransferases (NAT2A and NAT2B) whose liver contents correlate with acetylator phenotype in human populations [25].
  • The results provide strong evidence that the NAT2 locus is the site of the human acetylation polymorphism [25].
  • Under conditions designed to optimize enzyme stability, anion exchange chromatography experiments revealed that enzymes corresponding to both recombinant NAT1 and NAT2 were expressed in human liver [25].

Anatomical context of NAT2

  • The cell line, ANP-25, which expressed both CYP1A2 and NAT2, was approximately 370- and 100-fold more sensitive to IQ and MeIQx, respectively, than parental CR-68 cells in cytotoxicity assays [26].
  • This could be explained by the lack of detectable NAT2-associated sulfamethazine acetylation activity in cytosols prepared from mammary tissue, suggesting a minor contribution to carcinogen activation [27].
  • Immunohistochemical staining of sections of breast tissue identified expression of NAT1 and NAT2 protein in human mammary epithelial cells, but not in the stroma [28].
  • Basal and induced micronucleus frequencies in human lymphocytes with different GST and NAT2 genetic backgrounds [29].
  • Hybridization histochemistry studies have also demonstrated variable NAT1 and NAT2 expression in the human gastrointestinal tract [30].

Associations of NAT2 with chemical compounds

  • In addition, the use of recombinant NAT1 and NAT2 will allow us to predict whether any given arylamine will be polymorphically acetylated in humans [25].
  • Recombinant NAT2 and the liver NAT2 isoforms NAT2A and NAT2B selectivity N-acetylated the "polymorphic" substrates sulfamethazine and procainamide, whose disposition in vivo is affected by the acetylation polymorphism [25].
  • Interestingly, the carcinogen 2-aminofluorene was very efficiently metabolized by both NAT1 and NAT2 [25].
  • In addition, all case patients and matched control subjects were asked to donate an overnight urine specimen following caffeine consumption for measurements of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) phenotypes [31].
  • N-Acetyltransferase (NAT) activities, using p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) as substrates, were <5-5,500 and <5-43 pmol/min/mg cytosolic protein, respectively [32].

Physical interactions of NAT2


Enzymatic interactions of NAT2

  • Recent findings presented here may account for the genotype/phenotype relationship for the NAT1 locus being less clear-cut than that for human NAT2 [34].
  • In sonicate from transiently transfected COS cells, NAT1 increased CYP1A2 catalyzed adduct formation 4-fold while NAT2 increased adduct formation 12-fold [35].

Regulatory relationships of NAT2

  • The expression of these enzymes is tissue-specific such that NAT1 is ubiquitously expressed and NAT2 is confined mainly to liver and colorectal tissues [36].
  • The cytochrome P4501A2 (CYP1A2) enzyme and the bimodally expressed enzyme N-acetyltransferase2 (NAT2) metabolize many procarcinogens/carcinogens [37].

Other interactions of NAT2

  • As the next step, the A2R-5 as well as CR-68 cells were further transfected with human monomorphic NAT (NAT1) or polymorphic NAT (NAT2) cDNAs [26].
  • Four polymorphisms showed significant association with PD: slow acetylator genotypes of NAT2 (PD:control OR = 1.36), allele >188bp of the MAOB (GT)n polymorphism (OR = 2.58), the deletion allele of GSTT1 (OR = 1.34), and A4336G of tRNAGlu (OR = 3.0) [38].
  • CONCLUSION: Significant associations with PD were found in polymorphisms of NAT2, MAOB, GSTT1, and tRNAGlu [38].
  • Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias [39].
  • Genetic polymorphisms of CYP1A1 and NAT2 were also significantly correlated with the frequency of certain types of DNA adducts [40].

Analytical, diagnostic and therapeutic context of NAT2


  1. Analysis of candidate modifier loci for the severity of colonic familial adenomatous polyposis, with evidence for the importance of the N-acetyl transferases. Crabtree, M.D., Fletcher, C., Churchman, M., Hodgson, S.V., Neale, K., Phillips, R.K., Tomlinson, I.P. Gut (2004) [Pubmed]
  2. NAT2 slow acetylation and GSTM1 null genotypes may increase postmenopausal breast cancer risk in long-term smoking women. van der Hel, O.L., Peeters, P.H., Hein, D.W., Doll, M.A., Grobbee, D.E., Kromhout, D., Bueno de Mesquita, H.B. Pharmacogenetics (2003) [Pubmed]
  3. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Sachse, C., Smith, G., Wilkie, M.J., Barrett, J.H., Waxman, R., Sullivan, F., Forman, D., Bishop, D.T., Wolf, C.R. Carcinogenesis (2002) [Pubmed]
  4. Metabolic activation of the environmental contaminant 3-nitrobenzanthrone by human acetyltransferases and sulfotransferase. Arlt, V.M., Glatt, H., Muckel, E., Pabel, U., Sorg, B.L., Schmeiser, H.H., Phillips, D.H. Carcinogenesis (2002) [Pubmed]
  5. Effect of SULT1A1 and NAT2 genetic polymorphism on the association between cigarette smoking and colorectal adenomas. Tiemersma, E.W., Bunschoten, A., Kok, F.J., Glatt, H., de Boer, S.Y., Kampman, E. Int. J. Cancer (2004) [Pubmed]
  6. A meta-analysis of the association of N-acetyltransferase 2 gene (NAT2) variants with breast cancer. Ochs-Balcom, H.M., Wiesner, G., Elston, R.C. Am. J. Epidemiol. (2007) [Pubmed]
  7. Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study. Lubin, J.H., Kogevinas, M., Silverman, D., Malats, N., Garcia-Closas, M., Tardón, A., Hein, D.W., Garcia-Closas, R., Serra, C., Dosemeci, M., Carrato, A., Rothman, N. Int. J. Epidemiol (2007) [Pubmed]
  8. NAT gene polymorphisms and susceptibility to Alzheimer's disease: identification of a novel NAT1 allelic variant. Johnson, N., Bell, P., Jonovska, V., Budge, M., Sim, E. BMC Med. Genet. (2004) [Pubmed]
  9. N-Acetyltransferase 2 polymorphisms, cigarette smoking and alcohol consumption, and oral squamous cell cancer risk. Chen, C., Ricks, S., Doody, D.R., Fitzgibbons, E.D., Porter, P.L., Schwartz, S.M. Carcinogenesis (2001) [Pubmed]
  10. Increased frequency of wild-type arylamine-N-acetyltransferase allele NAT2*4 homozygotes in Portuguese patients with colorectal cancer. Gil, J.P., Lechner, M.C. Carcinogenesis (1998) [Pubmed]
  11. N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC). Pistorius, S., G??rgens, H., Kr??ger, S., Engel, C., Mangold, E., Pagenstecher, C., Holinski-Feder, E., Moeslein, G., von Knebel Doeberitz, M., R??schoff, J., Karner-Hanusch, J., Saeger, H.D., Schackert, H.K., The German Hnpcc-Consortium, n.u.l.l. Cancer Lett. (2006) [Pubmed]
  12. Assessment of frequencies of lifestyle factors and polymorphisms of drug-metabolizing enzymes (NAT2, CYP2E1) in human hepatocellular carcinoma (HCC) patients in a department of surgical medicine--a pilot investigation. Farker, K., Schotte, U., Scheele, J., Hoffmann, A. International journal of clinical pharmacology and therapeutics. (2002) [Pubmed]
  13. Molecular mechanisms of genetic polymorphisms of drug metabolism. Meyer, U.A., Zanger, U.M. Annu. Rev. Pharmacol. Toxicol. (1997) [Pubmed]
  14. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. Ambrosone, C.B., Freudenheim, J.L., Graham, S., Marshall, J.R., Vena, J.E., Brasure, J.R., Michalek, A.M., Laughlin, R., Nemoto, T., Gillenwater, K.A., Shields, P.G. JAMA (1996) [Pubmed]
  15. Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders. Hirvonen, A., Saarikoski, S.T., Linnainmaa, K., Koskinen, K., Husgafvel-Pursiainen, K., Mattson, K., Vainio, H. J. Natl. Cancer Inst. (1996) [Pubmed]
  16. A two-component nodule-specific enhancer in the soybean N23 gene promoter. Jørgensen, J.E., Stougaard, J., Marcker, K.A. Plant Cell (1991) [Pubmed]
  17. Nuclear factors interact with conserved A/T-rich elements upstream of a nodule-enhanced glutamine synthetase gene from French bean. Forde, B.G., Freeman, J., Oliver, J.E., Pineda, M. Plant Cell (1990) [Pubmed]
  18. Inhibitory effects of polyphenolic compounds on human arylamine N-acetyltransferase 1 and 2. Kukongviriyapan, V., Phromsopha, N., Tassaneeyakul, W., Kukongviriyapan, U., Sripa, B., Hahnvajanawong, V., Bhudhisawasdi, V. Xenobiotica (2006) [Pubmed]
  19. Arylamine N-acetyltransferase in erythrocytes of cystic fibrosis patients. Risch, A., Smelt, V., Lane, D., Stanley, L., van der Slot, W., Ward, A., Sim, E. Pharmacol. Toxicol. (1996) [Pubmed]
  20. Site-directed mutagenesis of recombinant human arylamine N-acetyltransferase expressed in Escherichia coli. Evidence for direct involvement of Cys68 in the catalytic mechanism of polymorphic human NAT2. Dupret, J.M., Grant, D.M. J. Biol. Chem. (1992) [Pubmed]
  21. Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses? Kinzig-Schippers, M., Tomalik-Scharte, D., Jetter, A., Scheidel, B., Jakob, V., Rodamer, M., Cascorbi, I., Doroshyenko, O., Sörgel, F., Fuhr, U. Antimicrob. Agents Chemother. (2005) [Pubmed]
  22. Orofacial clefts and spina bifida: N-acetyltransferase phenotype, maternal smoking, and medication use. van Rooij, I.A., Groenen, P.M., van Drongelen, M., Te Morsche, R.H., Peters, W.H., Steegers-Theunissen, R.P. Teratology (2002) [Pubmed]
  23. p53 mutations in bladder cancer: evidence for exogenous versus endogenous risk factors. Schroeder, J.C., Conway, K., Li, Y., Mistry, K., Bell, D.A., Taylor, J.A. Cancer Res. (2003) [Pubmed]
  24. Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk. Brockmöller, J., Cascorbi, I., Kerb, R., Roots, I. Cancer Res. (1996) [Pubmed]
  25. Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. Grant, D.M., Blum, M., Beer, M., Meyer, U.A. Mol. Pharmacol. (1991) [Pubmed]
  26. Stable expression of human CYP1A2 and N-acetyltransferases in Chinese hamster CHL cells: mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. Yanagawa, Y., Sawada, M., Deguchi, T., Gonzalez, F.J., Kamataki, T. Cancer Res. (1994) [Pubmed]
  27. Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression. Williams, J.A. Carcinogenesis (2001) [Pubmed]
  28. N-Acetyltransferases, sulfotransferases and heterocyclic amine activation in the breast. Williams, J.A., Stone, E.M., Fakis, G., Johnson, N., Cordell, J.A., Meinl, W., Glatt, H., Sim, E., Phillips, D.H. Pharmacogenetics (2001) [Pubmed]
  29. Basal and induced micronucleus frequencies in human lymphocytes with different GST and NAT2 genetic backgrounds. Hernández, A., Xamena, N., Gutiérrez, S., Velázquez, A., Creus, A., Surrallés, J., Galofré, P., Marcos, R. Mutat. Res. (2006) [Pubmed]
  30. The role of xenobiotic metabolizing enzymes in arylamine toxicity and carcinogenesis: functional and localization studies. Windmill, K.F., McKinnon, R.A., Zhu, X., Gaedigk, A., Grant, D.M., McManus, M.E. Mutat. Res. (1997) [Pubmed]
  31. Carotenoids/vitamin C and smoking-related bladder cancer. Castelao, J.E., Yuan, J.M., Gago-Dominguez, M., Skipper, P.L., Tannenbaum, S.R., Chan, K.K., Watson, M.A., Bell, D.A., Coetzee, G.A., Ross, R.K., Yu, M.C. Int. J. Cancer (2004) [Pubmed]
  32. Expression of cytochromes P450 and glutathione S-transferases in human prostate, and the potential for activation of heterocyclic amine carcinogens via acetyl-coA-, PAPS- and ATP-dependent pathways. Di Paolo, O.A., Teitel, C.H., Nowell, S., Coles, B.F., Kadlubar, F.F. Int. J. Cancer (2005) [Pubmed]
  33. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Matullo, G., Guarrera, S., Carturan, S., Peluso, M., Malaveille, C., Davico, L., Piazza, A., Vineis, P. Int. J. Cancer (2001) [Pubmed]
  34. Regulation of the activity of the human drug metabolizing enzyme arylamine N-acetyltransferase 1: role of genetic and non genetic factors. Rodrigues-Lima, F., Dupret, J.M. Curr. Pharm. Des. (2004) [Pubmed]
  35. Activation of heterocyclic amines by combinations of prostaglandin H synthase-1 and -2 with N-acetyltransferase 1 and 2. Liu, Y., Levy, G.N. Cancer Lett. (1998) [Pubmed]
  36. Xenobiotic inducible regions of the human arylamine N-acetyltransferase 1 and 2 genes. Mitchell, K.R., Warshawsky, D. Toxicol. Lett. (2003) [Pubmed]
  37. Low CYP1A2 activity associated with testicular cancer. Vistisen, K., Loft, S., Olsen, J.H., Vallentin, S., Ottesen, S., Hirsch, F.R., Poulsen, H.E. Carcinogenesis (2004) [Pubmed]
  38. Variability and validity of polymorphism association studies in Parkinson's disease. Tan, E.K., Khajavi, M., Thornby, J.I., Nagamitsu, S., Jankovic, J., Ashizawa, T. Neurology (2000) [Pubmed]
  39. Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Lemos, M.C., Cabrita, F.J., Silva, H.A., Vivan, M., Plácido, F., Regateiro, F.J. Carcinogenesis (1999) [Pubmed]
  40. Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer. Firozi, P.F., Bondy, M.L., Sahin, A.A., Chang, P., Lukmanji, F., Singletary, E.S., Hassan, M.M., Li, D. Carcinogenesis (2002) [Pubmed]
  41. Association of genotypes of carcinogen-activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N-acetyltransferase NAT2, with urothelial cancer in a Japanese population. Ozawa, S., Katoh, T., Inatomi, H., Imai, H., Kuroda, Y., Ichiba, M., Ohno, Y. Int. J. Cancer (2002) [Pubmed]
  42. Arylamine N-acetyltransferase type 2 (NAT2), chromosome 8 aneuploidy, and identification of a novel NAT1 cosmid clone: an investigation in bladder cancer by interphase FISH. Stacey, M., Matas, N., Drake, M., Payton, M., Fakis, G., Greenland, J., Sim, E. Genes Chromosomes Cancer (1999) [Pubmed]
  43. Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) polymorphisms in susceptibility to bladder cancer: the influence of smoking. Okkels, H., Sigsgaard, T., Wolf, H., Autrup, H. Cancer Epidemiol. Biomarkers Prev. (1997) [Pubmed]
  44. Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Hamdy, S.I., Hiratsuka, M., Narahara, K., Endo, N., El-Enany, M., Moursi, N., Ahmed, M.S., Mizugaki, M. British journal of clinical pharmacology. (2003) [Pubmed]
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