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

• CONCLUSIONS: These results suggest that genetic polymorphisms in NAT1 and NAT2 do not influence susceptibility to Alzheimer's disease, although the increase in frequency of the NAT1*10 allele in Alzheimer's disease is worthy of further investigation [8].
• These data raise the possibility that NAT2 may be involved in the activation of one or more pro-carcinogens associated with alcohol consumption [9].
• Taken together, our results strongly indicate that NAT2 genotype, particularly NAT2*4 allele zygosity, constitutes an individual susceptibility trait associated with sporadic colorectal cancer development, probably due to the local dietary habits in Portugal [10].
• The individual differences in the NAT2 metabolic capacity are caused by allelic variants of the NAT2 gene which are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes [11].
• This pilot investigation examines the frequency of polymorphisms in selected genes (NAT2, CYP2E1) coding for xenobiotic metabolizing enzymes, and life-style habits (cigarette smoking, alcohol consumption) in 38 HCC patients [12].

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

• Phytochemicals including cinnamic acid derivatives, various classes of flavonoids and coumarins were tested for the inhibitory activity on NAT1 and NAT2 from human liver and the human cholangiocarcinoma cell line: KMBC cells [18].
• The increased clearance of sulphamethoxazole in cystic fibrosis patients appears unlikely to be due to erythrocyte arylamine N-acetyltransferase type 1 activity or to inheritance of alleles at either the NAT1 or NAT2 loci [19].
• The single coding exons of the cloned genes encoding two human arylamine N-acetyltransferases (NAT1 and NAT2) were amplified by expression-cassette polymerase chain reaction and subcloned into the tac promoter-based phagemid vector pKEN2 for production of the recombinant proteins in Escherichia coli strain XA90 [20].
• The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics [21].
• METHODS: In this case-control study of 45 mothers of orofacial cleft children, 39 mothers of spina bifida children and 73 control mothers, NAT2 acetylator status was determined by measuring urinary caffeine metabolites [22].

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

• XRCC3 apparently interacted with the N-acetyltransferase type 2 (NAT-2) genotype [33].

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

• In a case-control study for urothelial epithelial cancers, low activity alleles of NAT2 are overall high-risk alleles (OR 2.11; 95% CI 1.08-4.26) [41].
• In this study, fluorescence in situ hybridization (FISH) was used for study of the relationship between chromosome 8 deletions in the region of NAT1 and NAT2 and grade and stage of tumor in bladder cancer [42].
• NAT1 mRNA transcript levels were found to be two- to three-fold higher than mRNA transcripts of the NAT2 gene in reduction mammoplasty tissue and mammary epithelial cells [28].
• These compounds are acetylated by N-acetyltransferase 1 (NAT1) and 2 (NAT2), and epidemiological studies have shown that the slow NAT2 acetylator phenotype is associated with increased risk of bladder cancer and may be associated with decreased risk of colorectal cancer [43].
• TPMT*3C and NAT2 variants (*5,*6 and *7) were detected using an allele-specific real-time PCR assay [44].

References