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1.  Are polymorphisms of N-acetyltransferase genes susceptible to primary liver cancer in Luoyang, China? 
AIM: To identify whether the polymorphisms of the N-acetyltransferase (NAT) genes are susceptible to primary liver cancer (PLC) in Luoyang, a PLC low-incidence area of China.
METHODS: The NAT1 and NAT2 genotypes of 96 PLC cases and 173 controls were determined by PCR-RFLP. Both interaction between NAT1 or NAT2 and environmental risk factors were analyzed based on case control study.
RESULTS: Compared to the control group, the frequencies of alleles NAT1*3, NAT1*4, NAT1*10, NAT1*14B and alleles NAT2*4, NAT2*6, NAT2*7 in PLC group showed no statistically significant difference (χ2 = 2.61 and 4.16, respectively, both P>0.05). The frequencies of NAT1 genotypes NAT1*3/*3, NAT1*3/*4, NAT1*3/*10, NAT1*3/*14B, NAT1*4/*4, NAT1*4/*10, NAT1*4/*14B, NAT1*10/*10, NAT1*10/*14B, and NAT2 genotypes NAT2*4/*4, NAT2*4/*6, NAT2*4/*7, NAT2*6/*6, NAT2*6/*7 and NAT2*7/*7 also had no statistically significant difference between the two groups (χ2 = 11.86 and 2.94 respectively both, P>0.05). Neither the frequencies of rapid and slow NAT1 acetylators nor the frequencies of rapid and slow NAT2 acetylators were significantly different between the two groups (χ2 = 0.598 and 0.44, respectively, both P>0.05). The interaction between NAT1*10 and occupational exposures was found significant with an odds ratio of 3.40 (χ2 = 8.42, P = 0.004, OR 95%CI:1.03-11.22). But no interaction was found between NAT2 and any environmental risk factors.
CONCLUSION: The polymorphisms of NAT1 and NAT2 are not susceptible to PLC in Luoyang. Allele NAT1*10 interacts with occupational exposures.
PMCID: PMC4305687  PMID: 15770721
Polymorphisms; N-acetyltransferase genes; Primary liver cancer
2.  Arylamine N-acetyltransferase polymorphisms in Han Chinese patients with ankylosing spondylitis and their correlation to the adverse drug reactions to sulfasalazine 
Polymorphisms of Arylamine N-acetyltransferase (NAT) that contribute to diverse susceptibilities of some autoimmune diseases are also linked to the metabolism of several drugs including sulfasalazine (SSZ). The aim of this study was to investigate the distribution of NAT polymorphisms in Han Chinese patients with ankylosing spondylitis (AS) and their correlation to sulfasalazine-induced adverse drug reactions (ADRs).
Arylamine N-acetyltransferase 1 (NAT1) and arylamine N-acetyltransferase 2 (NAT2) genotypes were determined in 266 AS patients who received SSZ treatment and 280 healthy controls. The correlation between NAT polymorphisms and SSZ-induced ADRs was analyzed.
The co-occurrence frequency of NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. No positive correlations were detected between NAT polymorphisms and AS clinical features. The prevalence of SSZ-induced ADRs and drug withdrawal was 9.4% and 7.1%, respectively. The frequencies of overall ADRs, dose-related ADRs, and termination of drug treatment because of intolerance were higher in the NAT2 slow acetylator genotype carriers than in the fast-type carriers and in those with co-existence of NAT1 and NAT2 slow acetylator genotypes. Furthermore, the ADRs emerged earlier in the AS cases carrying both NAT1 and NAT2 slow acetylator genotypes.
The prevalence of co-occurring NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. The NAT2 slow acetylator genotype and co-existing NAT1 and NAT2 slow acetylator genotypes appear to be associated with higher risks of SSZ-induced ADRs.
PMCID: PMC4247704  PMID: 25413361
Arylamine N-acetyltransferases; Genetic polymorphism; Sulfasalazine; Ankylosing spondylitis; Adverse drug reactions
3.  Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery 
British Journal of Pharmacology  2014;171(11):2705-2725.
Arylamine N-acetyltransferases (NATs) are polymorphic drug-metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic human NAT loci show linkage disequilibrium. All mammalian Nat genes have an intronless open reading frame and non-coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite para-aminobenzoylglutamate (p-abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. Human NAT1 is strongly expressed in oestrogen receptor-positive breast cancer and may contribute to folate and acetyl CoA homeostasis. NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site-modulating specificity. Polymorphisms may cause unfolded protein. The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. NAT in Salmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly, nat is in a gene cluster essential for Mycobacterium tuberculosis survival inside macrophages. NAT inhibitors are a starting point for novel anti-tuberculosis drugs. Human NAT1-specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy. NAT inhibitors for co-administration with 5-aminosalicylate (5-AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5-AS from prodrugs including balsalazide.
PMCID: PMC4158862  PMID: 24467436
arylamine N-acetyltransferase; catalytic triad; acetyl CoA; tuberculosis; breast cancer; hydralazine; isoniazid; pharmacogenetics
4.  Association between polymorphisms at N-acetyltransferase 1 (NAT1) & risk of oral leukoplakia & cancer 
Background & objectives:
N-acetyltransferases 1 and 2 (NAT1 and NAT2) are important enzymes for metabolism of tobacco carcinogens. Due to polymorphisms, improper activities of these enzymes might lead to the formation of DNA adducts that may modulate risk of tobacco related oral precancer and cancer. Previously, it was shown that NAT2 polymorphisms did not modulate the risk of oral precancer and cancer. We undertook this study to check whether polymorphisms at NAT1 can modulate the risk of oral leukoplakia and cancer either alone or in combination with NAT2.
Genotypes at four SNPs on NAT1 were determined by TaqMan method in 389 controls, 224 leukoplakia and 310 cancer patients. Genotype data were analyzed to know haplotypes and acetylation status of individuals and, then to estimate the risk of diseases. Using our previously published NAT2 data, combination of NAT1 and NAT2 acetylation genotypes of patients and controls were also analyzed to estimate the risk of diseases.
Analysis of NAT1 genotype data revealed that 1088T and 1095C alleles exist in strong linkage disequilibrium (r2=0.97, P<0.0001) and SNPs are in Hardy-Weinberg Equilibrium (P=0.1). Wild type or normal acetylating and variant or rapid acetylating alleles were two major alleles (frequencies 0.62 and 0.36, respectively) present in the control population. NAT1 rapid acetylation could not modulate the risk of leukoplakia and cancer (OR=0.9, 95% CI: 0.6-1.3; OR=1.0, 95% CI: 0.7-1.4, respectively). Analysis of combined NAT1 and NAT2 acetylating data also showed no significant enhancement of the risk of diseases.
Interpretation & conclusions:
NAT1 rapid acetylation alone as well as combination of NAT1 rapid-NAT2 slow acetylation did not modulate the risk of oral precancer and cancer in our patient population. So, NAT1/NAT2 metabolized carcinogen products may not be involved in tobacco related oral precancer and cancer. It may be interpreted that large sample size as well as combination of polymorphisms at other candidate loci may be important to estimate the risk of a complex disease like oral cancer.
PMCID: PMC3516028  PMID: 23168701
Combination of polymorphisms; leukoplakia; NAT1; NAT2; oral cancer
5.  Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma 
BMC Medical Genetics  2007;8:28.
N-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD.
A case control study was performed with 729 Caucasian participants, 123 CRC, 201 CD, 167 UC, 15 IBD dysplasia/cancer and 223 controls. NAT1 and NAT2 genotyping were performed using Taqman based techniques. Eight single nucleotide polymorphisms (SNPs) were characterized for NAT1 and 7 SNPs for NAT2. Haplotype frequencies were estimated using an Expectation-Maximization (EM) method. Disease groups were compared to a control group for the frequencies at each individual SNP separately. The same groups were compared for the frequencies of NAT1 and NAT2 haplotypes and deduced NAT2 phenotypes.
No statistically significant differences were found for any comparison. Strong linkage disequilibrium was present among both the NAT1 SNPs and the NAT2 SNPs.
This study did not demonstrate an association between NAT1 and NAT2 polymorphisms and IBD or sporadic CRC, although power calculations indicate this study had sufficient sample size to detect differences in frequency as small as 0.05 to 0.15 depending on SNP or haplotype.
PMCID: PMC1903350  PMID: 17537267
6.  Expression of arylamine N-acetyltransferase in human intestine 
Gut  1998;42(3):402-409.
Background—Arylamine N-acetyltransferases in humans (NAT1 and NAT2) catalyse the acetylation of arylamines including food derived heterocyclic arylamine carcinogens. Other substrates include the sulphonamide 5-aminosalicylic acid (5-ASA), which is an NAT1 specific substrate; N-acetylation of 5-ASA is a major route of metabolism. NAT1 and NAT2 are both polymorphic. 
Aims—To investigate NAT expression in apparently healthy human intestines in order to understand the possible role of NAT in colorectal cancer and in the therapeutic response to 5-ASA. 
Methods—The intestines of four organ donors were divided into eight sections. DNA was prepared for genotyping NAT1 and NAT2 and enzymic activities of NAT1 and NAT2 were determined in cytosols prepared from each section. Tissue was fixed for immunohistochemistry with specific NAT antibodies. Western blotting was carried out on all samples of cytosol and on homogenates of separated muscle and villi after microdissection. 
Results—NAT1 activity of all cytosols was greater than NAT2 activity. NAT1 and NAT2 activities correlated with the genotypes of NAT1 and NAT2 and with the levels of NAT1 staining determined by western blotting. The ratio of NAT1:NAT2 activities showed interindividual variations from 2 to 70. NAT1 antigenic activity was greater in villi than in muscle. NAT1 was detected along the length of the villi in the small intestine. In colon samples there was less NAT1 at the base of the crypts with intense staining at the tips. 
Conclusions—The interindividual variation in NAT1 and NAT2 in the colon could affect how individuals respond to exposure to specific NAT substrates including carcinogens and 5-ASA. 

Keywords: arylamine N-acetyltransferase; 5-aminosalicylate; colorectal cancer; drug metabolism; inflammatory bowel disease; diet
PMCID: PMC1727045  PMID: 9577349
7.  Polymorphisms of arylamine N-acetyltransferase2 and risk of lung and colorectal cancer 
Genetics and Molecular Biology  2012;35(4):725-733.
The arylamine N-acetyltransferase 2 (NAT2) enzymes detoxify a wide range of naturally occurring xenobiotics including carcinogens and drugs. Point mutations in the NAT2 gene result in the variant alleles M1 (NAT2 *5A), M2 (NAT2*6A), M3 (NAT2*7) and M4 (NAT2 *14A) from the wild-type WT (NAT2 *4) allele. The current study was aimed at screening genetic polymorphisms of NAT2 gene in 49 lung cancer patients, 54 colorectal cancer patients and 99 cancer-free controls, using PCR-RFLP. There were significant differences in allele frequencies between lung cancer patients and controls in the WT, M2 and M3 alleles (p < 0.05). However, only M2 and M3 allele frequencies were different between colorectal cancer patients and controls (p < 0.05). There was a marginal significant difference in the distribution of rapid and slow acetylator genotypes between lung cancer patients and controls (p = 0.06 and p = 0.05, respectively), but not between colorectal cancer patients and controls (p = 1.0 and p = 0.95, respectively). Risk of lung cancer development was found to be lower in slow acetylators [odds ratio (OR): 0.51, 95% confidence interval (95% CI): 0.25, 1.02, p-value = 0.07]. No effect was observed in case of colorectal cancer. Our results showed that NAT2 genotypes and phenotypes might be involved in lung cancer but not colorectal cancer susceptibility in Jordan.
PMCID: PMC3526077  PMID: 23271930
NAT2; lung cancer; colorectal cancer; polymorphisms
8.  Genetic polymorphisms of N-acetyltransferase 1 and 2 and risk of cigarette smoking-related bladder cancer 
British Journal of Cancer  1999;81(3):537-541.
Aromatic amines from cigarette smoking or occupational exposure, recognized risk factors for bladder cancer, are metabolized by N-acetyltransferases (NAT). This study examined the association of (NAT) 1 and 2 genotypes with the risk of smoking-related bladder cancer. A total of 74 pathologically confirmed bladder cancer patients and 184 controls were serially recruited from the National Taiwan University Hospital. History of cigarette smoking and other risk factors for bladder cancer was obtained through standardized questionnaire interview. Peripheral blood lymphocytes were collected from each subject and genotyped for NAT1 and NAT2 by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Allele frequency distributions of NAT1 and NAT2 were similar between cases and controls. There was a significant dose–response relationship between the risk of bladder cancer and the quantity and duration of cigarette smoking. The biological gradients were significant among subjects carrying NAT1*10 allele or NAT2 slow acetylators, but not among NAT2 rapid acetylators without NAT1*10 allele. The results are consistent with the hypothesis that NAT1 and NAT2 might modulate the susceptibility to bladder cancer associated with cigarette smoking. © 1999 Cancer Research Campaign
PMCID: PMC2362925  PMID: 10507782
N-acetyltransferase 1; N-acetyltransferase 2; cigarette smoking; bladder cancer
9.  N-acetyltransferase 2 slow acetylator genotype associated with adverse effects of sulfasalazine in the treatment of inflammatory bowel disease 
N-acetyltransferase 2 (NAT2) is an important enzyme catalyzing N-acetylation of sulfasalazine (SASP). The aim of the present study was to investigate associations of the genotypes of NAT2 with inflammatory bowel disease (IBD), and with adverse effects of SASP, which is used as the first-line treatment of IBD.
The wildtype allele (NAT2*4) and three variant alleles (NAT2*5B, NAT2*6A and NAT*7B) of the NAT2 gene were determined in 101 patients with IBD (84 patients with ulcerative colitis and 17 patients with Crohn’s disease) and 109 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism method. Sixty-eight patients with IBD treated with SASP were followed, and their adverse reactions were recorded.
Eleven patients (16%) experienced adverse effects from SASP, including nine cases of sulfapyridine (SP) dose-related adverse effects and two cases of hypersensitivity (skin rash). Patients with the slow acetylator genotypes without the NAT2*4 allele experienced adverse effects more frequently (36%) than those with the fast acetylator genotypes with at least one NAT2*4 allele (11%), but the results were not significantly different (OR of 0.26, 95% CI 0.065 to 1.004; P=0.051). However, those with the slow acetylator genotypes experienced more SP dose-related adverse effects than those with the fast acetylator genotypes (36% versus 8%, OR of 0.17, 95% CI 0.039 to 0.749; P=0.019).
The NAT2 gene polymorphism was not associated with susceptibility to IBD in Chinese populations, but the NAT2 slow acetylator genotypes were significantly associated with SP dose-related adverse effects of SASP in the treatment of IBD.
PMCID: PMC2657682  PMID: 17377643
Adverse effects; Genetic polymorphism; Inflammatory bowel disease; N-acetyltransferase 2; Sulfasalazine
10.  N-acetyltransferase 2 (NAT2) gene polymorphisms in colon and lung cancer patients 
BMC Medical Genetics  2006;7:58.
N-acetyltransferase 2 (NAT2) metabolizes arylamines and hydrazines moeities found in many therapeutic drugs, chemicals and carcinogens. The gene encoding NAT2 is polymorphic, thus resulting in rapid or slow acetylator phenotypes. The acetylator status may, therefore, predispose drug-induced toxicities and cancer risks, such as bladder, colon and lung cancer. Indeed, some studies demonstrate a positive association between NAT2 rapid acetylator phenotype and colon cancer, but results are inconsistent. The role of NAT2 acetylation status in lung cancer is likewise unclear, in which both the rapid and slow acetylator genotypes have been associated with disease.
We investigated three genetic variations, c.481C>T, c.590G>A (p.R197Q) and c.857G>A (p.G286E), of the NAT2 gene, which are known to result in a slow acetylator phenotype. Using validated PCR-RFLP assays, we genotyped 243 healthy unrelated Caucasian control subjects, 92 colon and 67 lung cancer patients for these genetic variations. As there is a recent meta-analysis of NAT2 studies on colon cancer (unlike in lung cancer), we have also undertaken a systematic review of NAT2 studies on lung cancer, and we incorporated our results in a meta-analysis consisting of 16 studies, 3,865 lung cancer patients and 6,077 control subjects.
We did not obtain statistically significant differences in NAT2 allele and genotype frequencies in colon cancer patients and control group. Certain genotypes, however, such as [c.590AA+c.857GA] and [c.590GA+c.857GA] were absent among the colon cancer patients. Similarly, allele frequencies in lung cancer patients and controls did not differ significantly. Nevertheless, there was a significant increase of genotypes [c.590GA] and [c.481CT+c.590GA], but absence of homozygous c.590AA and [c.590AA+c.857GA] in the lung cancer group. Meta-analysis of 16 NAT2 studies on lung cancer did not evidence an overall association of the rapid or slow acetylator status to lung cancer. Similarly, the summary odds ratios obtained with stratified meta-analysis based on ethnicity, and smoking status were not significant.
Our study failed to show an overall association of NAT2 genotypes to either colon or lung cancer risk.
PMCID: PMC1533812  PMID: 16827944
11.  The Role of N-Acetyltransferase 2 Polymorphism in the Etiopathogenesis of Inflammatory Bowel Disease 
Digestive Diseases and Sciences  2011;56(7):2073-2080.
Background and Purpose
Inflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn’s disease (CD), which are complex genetic disorders resulting from the interplay between several genetic and environmental risk factors. The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalyzed by NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. The aim of our study was to determine whether there is any association between the susceptibility to inflammatory bowel disease among the variations of NAT2 genotypes.
This study was carried out in 80 patients with IBD. The control group consisted of 100 healthy volunteers. The most common mutations found in the Caucasian population are at the positions 481T, 803G, 590A and 857A on the NAT2 gene. This was determined using the polymerase chain reaction–restriction fragment length polymorphism method with DNA extracted from peripheral blood.
Risk of IBD development was 3.86 for the carriers of the NAT2*5/NAT2*7 genotype and 2.53 for the carriers with NAT2*6/NAT2*7, but it was not statistically significant. A statistically significant correlation between the NAT2*7 allele prevalence and the risk for developing IBD was found (OR = 5.8; P = 0.005).
Higher prevalence of the NAT2*7 allele in patients with IBD and the obtained OR values could suggest that this mutation has the effect of increasing IBD development. Future studies are needed to confirm our assumptions on larger group of patients.
PMCID: PMC3112481  PMID: 21321790
Inflammatory bowel disease; NAT2; Genetic polymorphism
12.  Distribution of allelic and genotypic frequencies of NAT2 and CYP2E1 variants in Moroccan population 
BMC Genetics  2014;15(1):156.
Several pathogenesis and genetic factors influence predisposition to antituberculosis drug-induced hepatotoxicity (ATDH) especially for isoniazid (INH). However, the major susceptibility genes for ATDH are N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). NAT2 gene determines the individual’s acetylator status (fast, intermediate or slow) to metabolize drugs and xenobiotics, while CYP2E1 c1/c1 genotype carriers had an increased risk of ATDH.
Polymorphisms of the NAT2 and CYP2E1 genes vary remarkably among the populations of different ethnic origins.
The aim of this study was to determine, for the first time, the frequency of slow acetylators in Moroccan population by genotyping of NAT2 gene variants and determining the genotype c1/c1 for CYP2E1 gene, in order to predict adverse effects of Tuberculosis treatment, particularly hepatotoxicity.
The frequencies of specific NAT2 alleles were 53%, 25%, 2% and 4% for NAT2*5, NAT2*6, NAT2*7 and NAT2*14 respectively among 163 Moroccan studied group. Genotyping of CYP2E1 gene, by real-time polymerase chain reaction using TaqMan probes, revealed frequencies of 98.5% for c1/c1 and 1.5% for c1/c2 among 130 Moroccan studied group.
The most prevalent genotypes of NAT2 gene in Moroccans are those which encode slow acetylation phenotype (72.39%), leading to a high risk of ATDH. Most Moroccans are homozygous for c1 allele of CYP2E1 gene which aggravates hepatotoxicity in slow acetylators.
This genetic background should be taken into account in determining the minimum dose of INH needed to treat Moroccan TB patients, in order to decrease adverse effects.
PMCID: PMC4299568  PMID: 25544508
Tuberculosis; CYP2E1 gene; NAT2 gene; Polymorphism; Acetylators; Adverse effects; Moroccans
13.  Human N-acetyltransferase 1 (NAT1) *10 and *11 alleles increase protein expression via distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity 
Pharmacogenetics and genomics  2011;21(10):652-664.
N-acetyltransferase 1 (NAT1) metabolizes drugs and environmental carcinogens. NAT1 alleles *10 and *11 have been proposed to alter protein level or enzyme activity compared to wild-type NAT1 *4 and to confer cancer risk, via uncertain pathways. This study characterizes regulatory polymorphisms and underlying mechanisms of NAT1 expression.
We measured allelic NAT1 mRNA expression and translation, as a function of multiple transcription start sites, alternative splicing, and three 3′-polyadenylation sites in human livers (one of which discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 HIV/AIDS patients treated with the NAT1/NAT2 substrate sulfamethoxazole (SMX), associations were tested between SMX induced hypersensitivity and NAT1 *10 and *11 genotypes, together with known NAT2 polymorphisms.
NAT1*10 and *11 were determined to act as common regulatory alleles accounting for most NAT1 expression variability, both leading to increased translation into active protein. NAT1*11 (2.4% minor allele frequency) affected 3′polyadenylation site usage, thereby increasing formation of NAT1 mRNA with intermediate length 3′UTR (major isoform) at the expense of the short isoform, resulting in more efficient protein translation. NAT1 *10 (19% minor allele frequency) increased translation efficiency without affecting 3′-UTR polyadenylation site usage. Livers and B-lymphocytes with *11/*4 and *10/*10 genotypes displayed higher NAT1 immunoreactivity and NAT1 enzyme activity than the reference genotype *4/*4. Patients who carry *10/*10 and *11/*4 (‘fast NAT1 acetylators’) were less likely to develop hypersensitivity to SMX, but this was observed only in subjects also carrying a slow NAT2 acetylator genotype.
NAT1 *10 and *11 significantly increase NAT1 protein level/enzyme activity, enabling the classification of carriers into reference and rapid acetylators. Rapid NAT1 acetylator status appears to protect against SMX toxicity by compensating for slow NAT2 acetylator status.
PMCID: PMC3172334  PMID: 21878835
N-acetyltransferase; NAT1; polyadenylation; allelic expression imbalance; sulfamethoxazole; cotrimoxazole; protein translation; acetylator phenotype; idiosyncratic drug reactions
14.  N-acetyltransferase 2 genotype in colorectal cancer and selective gene retention in cancers with chromosome 8p deletions 
Gut  1997;41(2):229-234.
Background—Genetic polymorphisms in N-acetyltransferase (NAT2) can change the normally fast acetylation of substrates to slow acetylation, and have been associated with the development of some cancers. The NAT2 locus may also suffer dysregulation during cancer progression, as the gene resides on chromosome 8p22, a region which is frequently deleted in colorectal cancer. 
Subjects and Methods—A polymerase chain reaction based method was used to determine NAT2 genotype in 275 patients with colon cancer and 343 normal control DNAs. Within the cancer group, 65cases known to contain deletions in chromosome 8p were examined for loss of heterozygosity at the NAT2 locus. 
Results—Overall, there was no statistical difference in frequency or distribution of NAT2 alleles and genotype between colon cancer and control groups. There was a significant association between the slow acetylation genotype and early age of onset. NAT2 genotype did not vary with other clinical features of colon cancer, which included Dukes's stage, site of tumour, and sex. Of 48 informative cases, only three (6%) showed loss of heterozygosity, indicating that the NAT2 locus is not commonly deleted in colorectal cancer. This suggests that NAT2 is retained during the process of allele loss possibly because of its proximity to a gene necessary for cell viability. 
Conclusions—NAT2 does not play a major role in colorectal cancer risk, but may influence risk in some age groups. The nature of the loss of heterozygosity at the chromosome 8p site is complex and is worthy of further study. 

Keywords: xenobiotic; N-acetlytransferase 2; polymorphism; colorectal cancer; loss of heterozygosity; tumour suppressor gene
PMCID: PMC1891458  PMID: 9301503
15.  Tissue Expression and Genomic Sequences of Rat N-acetyltransferases rNat1, rNat2, rNat3, and Functional Characterization of a Novel rNat3*2 Genetic Variant 
Human arylamine N-acetyltransferases NAT1 and NAT2 are highly polymorphic genes that modify individual susceptibility to cancers caused by exposure to arylamine pro-carcinogens. Strong similarities exist between rat Nats and human NATs, and rat Nat2 polymorphisms result in slow acetylator phenotype. Recently, a third rat Nat, rNat3*1, was reported. Although in vivo toxicological and carcinogenic studies are often conducted in rats, relatively little is known about Nat sequences among available inbred rat strains. We report here that rNat1 and rNat2 open reading frames (ORFs) in twelve inbred rat strains (ACI, BN, BUF, CDF, COP, DA, LEW, LOU/M, MW, PVG, SHR, WF) corresponded to reference rNat1*13 and rNat2*20. While ten of the twelve strains had reference rNat3*1 ORFs, strains ACI and COP had a variant rNat3*2 ORF characterized by a G619>T transversion (A207S). The rNat3*2 SNP reduced Nat3 protein levels and N- and O-acetyltransferase activity when recombinantly expressed in bacteria. Recombinant expression of rNat3 1 and rNat3 2 in COS-1 cells yielded equivalent protein levels but undetectable catalytic activities. Relative tissue expression of rNat1, rNat2, and rNat3 mRNAs were assessed in liver and twelve extrahepatic tissues (lung, spleen, kidney, heart, esophagus, stomach, urinary bladder, prostate, colon, duodenum, jejunum, ileum) from male F344 rats exsanguinated prior to sacrifice. Semi-quantitative RT-PCR experiments demonstrate that the relative expression of the rNat transcripts in liver and twelve extrahepatic tissues was rNat1 > rNat2, while rNat3 transcripts were not detected. This study concludes that rNat1 and rNat2 are primarily responsible for acetylation phenotype in rats.
PMCID: PMC2094101  PMID: 17567587
Rat; N-acetyltransferase; tissue-specific; expression; rNat3
16.  Haplotype of N-Acetyltransferase 1 and 2 and Risk of Pancreatic Cancer 
We examined the association between N-acetyltransferase 1 and 2 (NAT1 and NAT2) haplotype and risk of pancreatic cancer by genotyping eight NAT1 and seven NAT2 single nucleotide polymorphisms in 532 patients and in 581 healthy controls (all non-Hispanic white) who were recruited at M. D. Anderson Cancer Center from January 2000 to December 2006. Haplotypes were reconstructed by using an expectation-maximization algorithm. Odds ratios and 95% confidence intervals were estimated by using unconditional logistic regression models. Covariates included age (continuous variable), sex, pack-year of smoking (categorical), and history of diabetes when appropriate. NAT1 and NAT2 genotype was mutually adjusted. The prevalence of haplotype NAT1*10-NAT2*6A was 4.3% versus 2.7% (P = 0.06) and NAT1*11-NAT2*6A was 1.2% versus 0.4% (P = 0.05) in patients and controls, respectively. The diplotype NAT1*10/*10 or NAT1*10/*11 and NAT2*6A/any slow allele was associated with a higher risk of pancreatic cancer compared with other diplotypes (multivariate odds ratio, 4.15; 95% confidence interval, 1.15-15.00; P = 0.03). NAT2 slow genotype were associated with increased risk of pancreatic cancer among heavy smokers and among individuals with a history of diabetes. We for the first time found that rare NAT1*10 or NAT1*11-NAT2*6A diplotype may be an “at-risk” genetic variant for pancreatic cancer. The NAT2*6A/any slow acetylation genotype may be a predisposing factor for pancreatic cancer among diabetics with smoking exposure. Our observations must be confirmed in larger independent studies.
PMCID: PMC2215308  PMID: 18006927
Head & neck  2008;30(9):1139-1147.
Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol.
We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs.
Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08–2.20; p value = .03). Gene–gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20–2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34–4.21, p value = .05).
These results implicate fast NAT2 acetylation as a risk factor for oral cancer.
PMCID: PMC3627181  PMID: 18642288
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
18.  Functional analysis of arylamine N-acetyltransferase 1 (NAT1) NAT1*10 haplotypes in a complete NATb mRNA construct 
Carcinogenesis  2011;33(2):348-355.
N-acetyltransferase 1 (NAT1) catalyzes N-acetylation of arylamines as well as the O-acetylation of N-hydroxylated arylamines. O-acetylation leads to the formation of electrophilic intermediates that result in DNA adducts and mutations. NAT1*10 is the most common variant haplotype and is associated with increased risk for numerous cancers. NAT1 is transcribed from a major promoter, NATb, and an alternative promoter, NATa, resulting in messenger RNAs (mRNAs) with distinct 5′-untranslated regions (UTRs). To best mimic in vivo metabolism and the effect of NAT1*10 polymorphisms on polyadenylation usage, pcDNA5/Flp recombination target plasmid constructs were prepared for transfection of full-length human mRNAs including the 5′-UTR derived from NATb, the open reading frame and 888 nucleotides of the 3′-UTR. Following stable transfection of NAT1*4, NAT1*10 and an additional NAT1*10 variant (termed NAT1*10B) into nucleotide excision repair-deficient Chinese hamster ovary cells, N- and O-acetyltransferase activity (in vitro and in situ), mRNA and protein expression were higher in cells transfected with NAT1*10 and NAT1*10B than in cells transfected with NAT1*4 (P < 0.05). Consistent with NAT1 expression and activity, cytotoxicity and hypoxanthine phosphoribosyl transferase mutants following 4-aminobiphenyl exposures were higher in NAT1*10 than in NAT1*4 transfected cells. Ribonuclease protection assays showed no difference between NAT1*4 and NAT1*10. However, protection of one probe by NAT1*10B was not observed with NAT1*4 or NAT1*10, suggesting additional mechanisms that regulate NAT1*10B. The higher mutants in cells transfected with NAT1*10 and NAT1*10B are consistent with an increased cancer risk for individuals possessing NAT1*10 haplotypes.
PMCID: PMC3271262  PMID: 22114069
19.  Should We Use N-Acetyltransferase Type 2 Genotyping To Personalize Isoniazid Doses? 
Isoniazid is metabolized by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 ± 6 years, body weight 74 ± 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. 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. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) = 10 + 9 × (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.
PMCID: PMC1087660  PMID: 15855489
20.  Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria 
Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9*3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.
PMCID: PMC3178826  PMID: 21966608
Aspirin; Cytochrome P4502C9; Metabolizing enzyme; Urticaria
21.  Association of Polymorphism in Cytochrome P450 2D6 and N-Acetyltransferase-2 with Parkinson’s Disease 
Disease markers  2010;28(2):87-93.
The present case-control study was carried out to investigate the association of polymorphism in cytochrome P450 2D6 (CYP2D6) and N-acteyltransferase-2 (NAT2), that are involved in the metabolism and detoxification of chemicals causing Parkinson disease (PD) like symptoms, with PD. Our data demonstrated increased frequency of CYP2D6*2 (1749G/C and 2938C/T), CYP2D6*4 (1934G/A) and CYP2D6*10A (188C/T) polymorphisms in PD cases when compared to the controls. Statistical analysis revealed the significant association of CYP2D6*4 (1934G/A) and CYP2D6*10A (188C/T) polymorphism with PD. Likewise, increased frequency of NAT2*7 polymorphism that leads to the slow acetylator phenotype was observed in PD patients with more than fivefold increased risk (OR: 5.55; 95%CI: 0.56–54). No change was observed in the frequency of NAT*5 or NAT*6 alleles in the cases. Further, cases carrying combination of heterozygous genotypes of CYP2D6*4 or CYP2D6*10A(188C > T) and NAT2*5 were found to be at significantly higher risk for PD demonstrating the importance of gene-gene interactions in determining susceptibility to PD.
PMCID: PMC3833242  PMID: 20364044
Cytochrome P450 2D6; N-acetyltransferase-2; poor metabolizers; parkinson disease; risk
22.  Role of N-acetyltransferase polymorphisms in hepatitis B related hepatocellular carcinoma: impact of smoking on risk 
Yu, M | Pai, C | Yang, S | Hsiao, T | Chang, H | Lin, S | Liaw, Y | Chen, P | Chen, C
Gut  2000;47(5):703-709.
BACKGROUND—Persistent infection with hepatitis B virus (HBV) causes chronic phasic necroinflammation and regenerative proliferation in the liver. The sustained hepatocellular proliferation may render chronic HBV carriers more susceptible to the effects of environmental carcinogens. Aromatic amines are potential hepatocarcinogens in humans. N-acetyltransferase (NAT) is involved in the metabolic activation and detoxification of these compounds.
AIMS—To investigate if genetic polymorphisms in N-acetylation are related to hepatocellular carcinoma (HCC) among chronic HBV carriers.
METHODS—Genotyping of NAT1 and NAT2 was performed using polymerase chain reaction-restriction fragment length polymorphism on peripheral leucocyte DNA from 151 incident cases of HCC and 211 controls. All subjects were male, and were chronic HBV surface antigen carriers.
RESULTS—A significant association between NAT2 genetic polymorphism and HCC was observed among chronic HBV carriers who were smokers but not among those who were non-smokers. For smoking HBV carriers, the odds ratios of developing HCC for those heterozygous and homozygous for the NAT2*4 functional allele compared with those without any copies of the functional allele (reference group) were 2.67 (95% confidence interval 1.15-6.22) and 2.58 (95% confidence interval 1.04-6.43), respectively. The interaction between cigarette smoking and the presence of the NAT2*4 allele just failed to reach statistical significance (p=0.06). No association between NAT1 genotype and HCC was evident overall or within the smoking stratified subgroups.
CONCLUSIONS—Our results suggest that NAT2 activity may be particularly critical in smoking related hepatocarcinogenesis among chronic HBV carriers. Our data also indirectly support a role for tobacco smoke derived aromatic amines in the aetiology of HCC.

Keywords: genetic polymorphism; hepatocellular carcinoma; N-acetyltransferase; smoking
PMCID: PMC1728099  PMID: 11034589
23.  Deletion of a xenobiotic metabolizing gene in mice affects folate metabolism 
The mouse arylamine N-acetyltransferase 2 (Nat2) and its homologue (NAT1) in humans are known to detoxify xenobiotic arylamines and are also thought to play a role in endogenous metabolism. Human NAT1 is highly over-expressed in estrogen receptor positive breast tumours and is implicated in susceptibility to neural tube defects. In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking. Mouse Nat2 provides a good model to study human NAT1 as it shows similar expression profiles and substrate specificities. We have generated transgenic mice lacking a functional Nat2 gene and compared the urinary levels of acetylated folate metabolite para-aminobenzoylglutamate in Nat2 knockout and Nat2 wild-type mice. These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism. In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described.
PMCID: PMC2315789  PMID: 17961509
NAT/arylamine N-acetyltransferase; folate; NTD; gender; sex ratio; breast cancer
24.  Deletion of a xenobiotic metabolizing gene in mice affects folate metabolism 
The mouse arylamine N-acetyltransferase 2 (Nat2) and its homologue (NAT1) in humans are known to detoxify xenobiotic arylamines and are also thought to play a role in endogenous metabolism. Human NAT1 is highly over-expressed in estrogen receptor positive breast tumours and is implicated in susceptibility to neural tube defects. In vitro assays have suggested an endogenous role for human NAT1 in folate metabolism, but in vivo evidence to support this hypothesis has been lacking. Mouse Nat2 provides a good model to study human NAT1 as it shows similar expression profiles and substrate specificities. We have generated transgenic mice lacking a functional Nat2 gene and compared the urinary levels of acetylated folate metabolite para-aminobenzoylglutamate in Nat2 knockout and Nat2 wild-type mice. These results support an in vivo role for mouse Nat2/human NAT1 in folate metabolism. In addition, effects of the Nat2 deletion on sex ratios and neural tube development are described.
PMCID: PMC2315789  PMID: 17961509
NAT/arylamine N-acetyltransferase; Folate; NTD; Gender; Sex ratio; Breast cancer
25.  N-acetyltransferase 2 and bladder cancer: an overview and consideration of the evidence for gene–environment interaction 
British Journal of Cancer  2000;83(3):412-417.
Genetic polymorphism of the carcinogen metabolizing enzyme N -acetyl transferase 2 (NAT2) may influence susceptibility to bladder cancers related to smoking or to occupational exposure to arylamine carcinogens. This article reviews the results of 21 published case–control studies of NAT2 polymorphism and bladder-cancer risk, with a total of 2700 cases and 3426 controls. The published evidence suggests that NAT2 slow acetylator phenotype or genotype may be associated with a small increase in bladder cancer risk. However, given the possibility of selective publication of results from studies that found an excess risk, the current evidence is not sufficient to conclude that there is a real increase in risk. Only five of the 21 studies reported results separately for the effect of NAT2 on bladder cancer risk in smokers and non-smokers. Although the results suggest that the effect may be greater in smokers than in non-smokers, the possibility of publication bias makes these results difficult to interpret. There was insufficient evidence to assess the joint effect of NAT2 and occupational exposure to arylamines on bladder cancer risk. Even if estimates of the effect of NAT2 from published data are correct, studies with around 3000–5000 cases will be needed to confirm them. © 2000 Cancer Research Campaign
PMCID: PMC2374558  PMID: 10917561
bladder cancer; NAT2; genetic polymorphism; smoking; arylamines; gene–environment interaction

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