N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.

Background & objectives: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. Methods: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. Results: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. Interpretation & conclusions: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.

NAT2 gene polymorphisms in three indigenous groups in the Colombian Caribbean Coast region / Polimorfismo del Gen NAT2 en tres grupos indígenas de la región Caribe Colombiana

Objective: To study the NAT2 gene polymorphisms 481T, 590A and 857A in the Chimila, Wiwa and Wayuu indigenous groups of the Colombian Caribbean to determine the frequencies of the alleles NAT2*4, NAT2*5, NAT2*6, and NAT2*7 and to determine the types of acetylators present in these populations. Methods: A total of 202 subjects were studied: 47 Chimila, 55 Wiwa, and 100 Wayuu. The polymorphisms were identified using a real-time PCR method for allelic discrimination designed using Taqman of Applied Biosystems. Results: The following alleles were found at the highest frequency in the following groups: the NAT2*4 allele (wild type) in the Wayuu group (55.3%), the NAT2*5 allele in the Wiwa group (34.5%), and the NAT2*7 allele in the Chimila group (24.2%). A higher frequency of the rapid acetylator status was found in the Wayuu group (31.3%) and Chimila group (29.5%) compared with the Wiwa group (12.7%). The intermediate acetylator status distribution was very similar in all three groups, and the frequency of the slow acetylator status was higher in the Wiwa group (32.7%) compared with the Chimila and Wayuu groups (20.5% and 21.2%, respectively). Conclusion: The results demonstrated the allelic distribution and pharmacogenetic differences of the three groups studied and revealed the most frequent acetylator status and phenotype. Because of the high prevalence of slow acetylators, a greater incidence of tuberculosis (TB) drug-induced hepatotoxicity is predicted in these populations, with a higher frequency in the Wiwa group.

Objetivo: Estudiar los polimorfismos tipo SNP (del inglés- single nucleotide polymorphism) 481T, 590A y 857A del gen NAT2, en los grupos indígenas Chimila, Wiwa y Wayúu del Caribe Colombiano para determinar las frecuencias de los alelos NAT2*4, NAT2*5, NAT2*6 y NAT2*7 y caracterizar el tipo de acetiladores presentes en estas poblaciones. Métodos: Se estudiaron 202 individuos en total, 47 Chimila, 55 Wiwa y 100 Wayúu. Los polimorfismos se determinaron mediante la técnica de PCR en tiempo real por el método de discriminación alélica Taqman de Applied Biosystems. Resultados: El alelo NAT2*4 (wild type) mostró una mayor frecuencia en el grupo Wayúu (55.3%), el alelo NAT2*5 en el grupo Wiwa (34.5%) y el alelo NAT2*7 en el grupo Chimila (24.2%). Se encontró una mayor frecuencia del estado acetilador rápido en el grupo Wayúu (31.3%) y en el grupo Chimila (29.5%) al compararse con el grupo Wiwa (12.7%). La distribución del estado acetilador intermedio es muy similar en los tres grupos, y para el estado acetilador lento observamos que en el grupo Wiwa la frecuencia es mayor (32.7%) con respecto a Chimila y Wayúu con 20.5% y 21.2% respectivamente. Conclusiones: Los resultados permitieron conocer la distribución alélica y el componente farmacogenético de los tres grupos estudiados; igualmente, deducir el estado acetilador y/o fenotipo más frecuente. Debido a la alta prevalencia de acetiladores lentos, se podría predecir un aumento de la incidencia de hepatotóxicidad inducida por medicamentos antituberculosos como la Isoniacida indicados en estas poblaciones y en mayor frecuencia en el grupo Wiwa.

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. Methods: 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. Results: 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.

Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22 percent (18/82) vs. 9.8 percent (6/61), odds ratio (OR), 2.86, 95 percent confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95 percent CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

N-acetyltransferase2 genotype and its association with hepatitis among Filipino children treated with first line anti-tuberculosis drugs

RATIONALE: Among the first line antituberculosis (anti-TB) drugs, the major drug incriminated in the development of hepatotoxicity is isoniazid (INH). The human N-acetyl transferase2 (NAT2) gene is mainly responsible for INH metabolism. This gene exhibits a hereditarily determined polymorphism. There is presently no study on the predominant NAT2 genotype among Filipinos. There are also no Filipino studies on the incidence of hepatitis and other adverse effects of first line anti-TB drugs. OBJECTIVES: To determine the predominant NAT2 genotype and its association with the development of hepatitis among Filipino children given first line anti-TB drugs (INH, rifampicin and pyrazinamide) and to determine the incidence of hepatitis and other serious adverse reactions to these drugs. STUDY DESIGN: Prospective cohort study SETTING: Tertiary government hospital in Metro Manila STUDY POPULATION: Children on to 18 years old with pulmonary tuberculosis and normal liver function test at baseline. METHODS: Total bilirubin (TB), direct bilirubin (DB) and liver transaminases (AST and ALT) were checked routinely at baseline and at thow, four, eight and 12 weeks after starting treatment. Within the first month of treatment, blood was also taken for NAT2 genotyping. The identification of the three NAT2 polymorphisms that are associated with a slow acetylator status - 481C to T (NAT2*5), 950G to A (NAT2*6) and 857G to A (NAT2*7) was carried out by polymerase chain reaction-restriction fragment length polymorphism. All patients were followed up for a total of six months. The presense of any adverse effects like gastroinstestinal symptoms, rash, hepatitis or drug fever was also monitored. RESULTS: A total of 24 children [mean age: 5 years; 11 males] were included. Majority (96%) were diagnosed by passive detection and mean Z score was - 1.38 (1 to -3). No patient developed hepatotoxicity or any side effects to anti-TB drugs. In 23 patients who had NAT2 genotyping, 39% and 22% were alleles homozygous for the NAT2*6 and NAT2*7, respectively. There was a combination of alleles in only three (13%) subjects. CONCLUSION: NAT2*6 and NAT2*7 alleles associated with a slow acetylator status were detected among our patients although the presence of these variants did not lead to any hepatotoxicity nor any treatment-related side effects. A larger study with broader genotype analysis is needed to confirm the present findings.

Relationship between polymorphism of arylamine N-acetyltransferase 2 and genetic susceptibility to hair dye dermatitis / 中华医学美学美容杂志

Objective To investigate the relationship between polymorphism of arylamine N-acetyltransferase 2 (NAT2) and hair dye dermatitis in a Chinese population. Methods Polymorphism chain-restriction fragment length polymorphism (PCR-RFLP) was used and the wild-type allele (NAT2 * 4) and three mutant alleles (NAT2 * 5A, 6B and 7A) were determined in 60 patients with hair dye dermatitis and 73 age-matched control subjects in Tianjin region. Results In hair dye dermatitis cases, the frequency of NAT2 * 4, NAT2 * 5A, NAT2 * 6B, NAT2 * 7A was 52. 5 % , 5. 0 % ,26.7 % and 15. 8 %, respectively, and no statistically significant difference of the frequencies was found between the hair dye dermatitis patients and controls (P>0. 05). The frequency of rapid genotype, intermediate genotype and slow genotype was 26. 7 % , 51. 7 % and 21. 7 % in hair dye dermatitis cases, 30. 1 %, 50. 7 % and 19. 2 % in control subjects, respectively, and no statistically significant difference of the frequencies between the two groups (P>0. 05). Conclusions Our study suggests that there might be no relationship between polymorphism of NAT2 and genetic susceptibility to hair dye dermatitis in a Chinese population.

Allelic frequencies of single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene of Filipinos

OBJECTIVES:The present study aims to determine the frequency of occurrence of NAT2*4, NAT2*5A, NAT2*6B, NAT2*7A and NAT2*14A alleles by PCR-RFLP among Filipino volunteers. These alleles correspond to substitutions in the following sites: C341T, G590A, G857A and G191A, respectively, of the NAT2 gene. The presence of specific SNP combination was also used to deduce acetylation status and estimate genotype frequency and describe them in comparison with other populations based on literature. METHODS: Genomic DNA from peripheral blood lymphocytes from 129 healthy Filipino volunteers was used to amplify the NAT2 gene segment. The RFLP analysis was done by restricting the expected PCR product with Kpn1, Taq1, BamH1 and Msp1/Al1, respectively, to detect the 4 alleles: NAT2*4, NAT2*5A, NAT2*6B, NAT2*7A and NAT2*14A. RESULTS:The calculated allelic frequencies in Hardy-Weinberg equilibrium of NAT2*5A (C481T), NAT2*6B (G590A), NAT2*7A (G857A) and NAT2*14A (G191A) were 0.058, 0.097, 0.182 and 0.046, respectively. NAT2*4 had an allele frequency of 0.617. Nine genotypes were determined: NAT2*4/*4, NAT2*4/*5A, NAT2*4/*6B, NAT2*4/*7A, NAT2*4/*14A, NAT2*5A/*7A, NAT2*6B/*7A, NAT2*6B/*14A and NAT2*7A/*14A. From these genotypes, acetylator phenotypes were deduced. A trimodal pattern of distribution was established: rapid, intermediate and slow acetylators with the following percentages, 47.3%, 41.1 % and 11.6%. Among the slow acetylator SNPs determined, NAT2*7A was found as the most frequent allele and NAT2*14A was found as the least frequent allele. CONCLUSION:The study showed the mutation profile and observed genotypic similarities and differences of Filipinos with other Asian populations and Americans and other Caucasians based on literature. The results also suggest a trimodal pattern of distribution of acetylators and lesser number of slow acetylators among Filipino populations, a characteristic similar to other Asian populations but significantly different from Americans and other Caucasians. The occurrence of NAT2*7A and NAT2*14A can be further sequenced to verify the observed genotype.

The Effect of Genotype of NAT2, TNF-alpha and TGF-beta Genes on Allergic Rhinitis in Korea / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: The inflammatory reaction is affected by the genotype or phenotype of genes related with inflammation modulating cytokines and allergen metabolizing enzyme. This study was performed to investigate the relationship between N-acetyl transferase 2 (NAT2), tumor necrosis factor-alpha(TNF-alpha), transforming growth factor-beta(TGF-beta) and the allergic rhinitis in Korea. SUBJECTS AND METHOD: One hundred forty five allergic rhinitis patients and 167 controls were included. Venous blood samples were collected and the genotypes were analyzed by PCR technique. NAT2 phenotypes were designated as 'high', 'medium' and 'low' by known genotype-phenotype relationship. TNF-alpha genotypes were classified as 'A/A', 'A/G' and 'G/G'. TGF-beta genotype was classified as 'Arg/Arg', 'Arg/Pro' and 'Pro/Pro'. These data were analyzed by SAS for windows ver 8.02. RESULTS: The phenotype of NAT2 and genotype of TGF-beta showed no significant effect on allergic rhinitis. G/G or G/A genotype of TNF-alpha significantly increases the risk of allergic rhinitis. High activity phenotype of NAT2 showed higher level of total serum IgE. CONCLUSION: Genetic factors including TGF-beta are important in the development of allergic rhinitis in Korea. NAT2 phenotype affect allergic reaction.

The Association between Pneumoconiosis and Genetic Polymorphism of GSTM1, GSTT1, GSTP1, NAT2, CYP2E1 and CYP1A1 / 대한산업의학회지

OBJECTIVES: To investigate effects of genetic polymorphism of glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), glutathione S-transferase P1 (GSTP1), N-acetyltransferase (NAT2), cytochrome P450 2E1 (CYP2E1) and cytochrome P450 1A1 (CYP1A1) on pneumoconiosis. METHODS: Eighty-five pneumoconiosis patients and 122 age and sex matched healthy controls were enrolled. Direct interview and standard questionnaire were conducted and the genotypes of GSTM1, GSTT1, GSTP1, NAT2, CYP2E1 and CYP1A1 were investigated using multiplex PCR or PCR-RFLP methods with DNA extracted from venous blood. The relationship was investigated between the severity of pneumoconiosis and the polymorphism of GSTM1, GSTT1, GSTP1, NAT2, CYP2E1 and CYP1A1, and also with various environmental factors including smoking. RESULTS: We observed a significantly higher rate of genetic polymorphism in pneumoconiosis patients than in normal subjects. The odds ratio (95% CI) of NAT2 was 2.09 (1.19-3.68). In addition, smoking was related significantly with pneumoconiosis (OR 2.89, 95% CI 1.40-5.95). In multiple logistic regression analyses, NAT2 and smoking were significant risk factors for the development of pneumoconiosis (OR 1.84, 95% CI 1.00-3.37; OR 2.98, 95% CI 1.40-6.35, respectively). The age of onset of the disease and smoking were significantly related with moderate or severe pneumoconiosis (OR 0.91, 95% CI 0.83-0.99; OR 6.94, 95% CI 1.54-31.30, respectively). However there was no significant difference between the rate of genetic polymorphism of GSTM1, GSTT1, GSTP1, CYP2E1 and CYP1A1 in the two groups. CONCLUSION: NAT2 genetic polymorphism was higher in pneumoconiosis patients than in normal subjects. The age of onset of the disease and smoking were significantly related with pneumoconiosis. However, the genetic polymorphism of GSTM1, GSTT1, GSTP1, CYP2E1 and CYP1A1 was not related with development or severity of pneumoconiosis.

Influences of Genetic Polymorphisms of Glutathione S-transferase M1 and T1, and N-acetyltransferase 2 on Colorectal Cancer Risk / 대한진단검사의학회지

BACKGROUND: Inherited polymorphisms that affect carcinogen metabolism may influence the risk for the development of colorectal cancer. This study was performed to evaluate the potential association between glutathione S-transferase M1 (GSTM1), GSTT1 and N-acetyltransferase 2 (NAT2) polymorphisms and colorectal cancer in Korea. METHODS: The frequencies of GSTM1, GSTT1, and NAT2 polymorphisms were compared between 98 patients with colorectal cancer and age and sex matched 98 healthy controls. GSTM1 and GSTT1 polymorphisms were simultaneously determined by multiplex polymerase chain reaction (PCR) and NAT2 polymorphisms were analyzed by real-time PCR with melting curve analysis. GSTM1 null, GSTT1 null and NAT2 rapid type were considered as risk genotypes. RESULTS: The prevalence of GSTM1 null genotype was 44.9% in the controls, and 58.2% in the cases (odds ratio, OR=1.706, P=0.086). The prevalence of GSTT1 null genotype in the controls and the cases was 48.0% and 54.1%, respectively (OR=1.278, P=0.475). NAT2 rapid type were found in 45.9% of healthy controls and 51.0% of cancer patients (OR=1.227, P=0.568). Relative risk for colorectal cancer increased significantly (P=0.032) as the number of risk genotypes increased. CONCLUSIONS: These results suggest that genetic polymorphisms of GSTM1, GSTT1 and NAT2 have no independent effect on colorectal cancer risk individually, but there exists a dose-response relationship between a combined number of the risk genotypes of GSTM1, GSTT1 and NAT2 and colorectal cancer risk.

Lack of association of NAT2 (N-acetyl transferase 2) gene polymorphism with atopic asthma in Turkish subjects.

It has been shown that slow acetylation may be a risk factor that influences the development of allergic diseases. N-acetyltransferase2 (NAT2), an enzyme that degrades autocoids and drugs, shows a bimodal distribution of rapid and slow acetylators with broad interethnic variation. This case-control study was designed to investigate the association of genotypes that encode slow and rapid activity of NAT2 with asthma and asthma severity in the Turkish population. Turkish unrelated atopic subjects with asthma (n=57) and unrelated healthy subjects (n=56) were enrolled in this case-control study. The locus coding for NAT2 was genotyped by means of the polymerase chain reaction. Multivariate logistic regression models were constructed to investigate the relationship between NAT2 genotypes and case-control status.The frequency of slow acetylators inferred from NAT2 genotype was not significantly different in asthmatic subjects (47%) and healthy subjects (43%) (P<0.55). No significant association was found between NAT2 genotype and either disease severity or duration within the case group (P<0.19 and P<0.17, respectively). This study suggests that the NAT2 (slow acetylation) genotype is not a marker of predisposition for atopic asthma and severity of asthma in the Turkish population.

Association between Endometriosis and Polymorphisms of N-acetyl Transferase 2 (NAT2), Glutathione S-transferase M1 (GSTM1) and Cytochrome P450 (CYP) 1A1 Genes in Korean Infertile Patients / 대한불임학회지

OBJECTIVE: To investigate the association between endometriosis and polymorphisms of N-acetyl transferase 2 (NAT2), glutathione S-transferase M1 (GSTM1), and cytochrome P450 (CYP) 1A1 genes in Korean infertile patients. MATERIALS AND METHODS: A total of 303 infertile patients who had undertaken diagnostic laparoscopy during January, 2001 through December, 2003 at Samsung Cheil Hospital enrolled in this study. The patients were grouped according to laparoscopic findings: minimal to mild endometriosis (group I: n=147), moderate to severe endometriosis (group II: n=57), normal pelvic cavity (n=99). Peripheral blood was obtained and genomic DNA was extracted. The genotypes of each genes were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). For NAT2, RFLP was used to detect the wild type (wt) and mutant (mt) alleles, enabling classification into slow (mt/mt) or fast (wt/wt or wt/mt) acetylation genotypes. For GSTM1, PCR was used to distinguish active (+/- or +/+) from null (-/-) genotypes. For CYP1A1, MspI digestion was used to detect the wild type (A1A1), heterozygote (A1A2) or mutant (A2A2) genotypes. RESULTS: The genotype frequencies of NAT2 slow acetylator was 12.8%, 10.9%, 12.8% in group I, group II and control, respectively. The genotype frequencies of GSTM1 null mutation was 55.3%, 41.8%, 53.2% in group I, group II and control, respectively. The genotype frequencies of CYP1A1 MspI polymorphism was 16.3%, 9.1%, 18.1% in group I, group II and control, respectively. No significant difference was observed between endometriosis and normal controls in the genotype frequencies of the NAT2, GSTM1, CYP1A1 MspI polymorphism. CONCLUSION: The NAT2, GSTM1, CYP1A1 gene polymorphism may not be associated with the susceptibility of endometriosis in Korean women.

Researches on drug metabolism enzyme NAT2 / 中国药理学通报

NAT2 is an important drug metabolizing enzymes in humans.Polymorphisms in NAT2 gene produce variants at amino acid including seven mutation sites.In vivo NAT2 takes part in 20 kinds of drugs metabolism and activation of carcinogen.Polymorphism of NAT2 has been related to some diseases.This paper reviews the polymorphisms and genotyping about NAT2 and their implications in drug and clinical research.

A reverse dot blot method for genotyping of NAT2 in Chinese subjects / 中国药理学通报

Aim To establish a simple reverse dot blot m ethod (RDB) for detecting the genotype of NAT2 in Chinese people. Methods PCR was performed to obtain a biotin labeled DNA fragment. Allele specific oligonucleotide probes were spotted onto a nylon membrane. The DNA fragment hybridized with the membrane under stringent conditions. Finally, a nonradioactive colorimetric reaction was used to detect five mutants of NAT2. NAT2 genotypes of 48 patients with pulmonary tuberculosis were detected with RDB.Results The results obtained from RDB were in consistent with those from allele specific amplification. The NAT2 allele frequencies of *5, *6, *7 were 1.04%, 22.9% and 15.6%, respectively.Homozygous wildtype,heterozygous mutant and homozygous mutant subjects were 33.3%, 54.2% and 12.5%, respectively.Conclusion RDB method was proved to be accurate and convenient, it can be u sed in rational drug therapy.

N-acetyl Transferase 2 Gene Polymorphisms in Patients with Endometriosis / 대한산부인과학회잡지

OBJECTIVE: To explore the association of the N-acetyl transferase 2 (NAT 2) gene polymorphisms with endometriosis. METHODS: One hundred seventy-two women with surgically or histologically diagnosed endometriosis of stages I-IV, and 205 patients with no evidence of endometriosis by laparoscopy or laparotomy served as control. Genotype distribution of NAT 2 polymorphisms and frequencies of slow and fast acetylators in affected women and controls were evaluated. RESULTS: There was no statistically significant difference in the genotype distribution of NAT 2 polymorphisms and frequencies of slow and fast acetylators between the patients with endometriosis and the controls. CONCLUSION: These results suggest that N-acetyl transferase 2 gene polymorphisms is not associated with the risk for endometriosis in the Korean population.

Effect of the Genetic Polymorphism of N-acetyltransferase 2 and Diet on the Carcinogenesis of Gastric Cancer in Koreans

PURPOSE: According to the recent studies on the carcinogenic factors of gastric cancer in Koreans, dietary factors, such as stew, roasted fish, and fish boiled in soy with spices, salted foods, as well as smoking, might be risk factors of gastric cancer. N-acetyltransferase 2 (NAT2) is an enzyme that plays a role in the reduction of the toxicity of various carcinogens. There is a possibility that the genetic polymorphism of NAT2 might change a subject's susceptibility to gastric cancer. The aim of this study was to examine the effects of diet, the genetic polymorphism of NAT2 and their interaction on the risk of gastric cancer in Koreans. METHODS: The subjects of this case-control study were 214 gastric cancer patients, and 214 controls, who were admitted at the Chungbuk National or Eulji University Hospitals. Each subject was directly interview, by an experienced interviewer, with a structured questionnaire. A NAT2 genetic polymorphism analysis was performed, with a PCR-RFLP technique, and the data analyzed using the PC-SAS software package. RESULTS: Increased intakes of makkoli, soybean paste stew, kimchi and ggakdugi, soy milk, chicken boiled with rice and boiled chicken were all associated with an increased risk of gastric cancer, whereas those of fermented soybean stew, Welsh onion or leek, onions, peaches, chestnuts or gingko nuts, fatsia shoots, raw fish, salted seafood and laver were all associated with a decreased risk of gastric cancer. The odds ratio (95% confidence interval) for gastric cancer for the rapid acetylators was 1.64 (1.12, 2.41), which was statistically significant. With respect to the rapid acetylators, makkoli, kimchi and soy milk were significant risk factors, and Welsh onion/leek and onions were protective factors for gastric cancer. Whereas, soybean paste stew was a risk factor of gastric cancer with the slow or intermediate acetylators. CONCLUSION: These results suggest the genotype of a rapid acetylation is a risk factor of gastric cancer, and the effects of diet on the risk of gastric cancer vary according to the genotype of the NAT2 enzyme.

CYP2D6 and NAT2 Polymorphism in HBV Associated in Hepatocellular Carcinoma Patients in Korea

PURPOSE: CYP2D6 and N-acetyltransferase (NAT2) are polymorphic enzymes which are expressed in the hepatocyte in a genotype-determined manner. They are known to be involved in the inactivation and activation of various mutagens and carcinogens, respectively. The activities of the two enzyme systems are associated with the genetic susceptibility of many human cancers. METHODS: This study was performed to determine the genotype frequencies of the two enzyme systems in primary hepatocellular carcinoma patients and healthy controls. One hundred healthy controls and 55 liver cancer patients were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: In the healthy controls, the CYP2D6 wild type allele frequency was 0.985 and the CYP2D6*4 frequency was 0.015. No CYP2D6 poor-metabolizer was detected. No significant differences were found in the hepatocellular carcinoma patients group. Among the controls, the frequencies of F, S1, S2 and S3 alleles of the NAT2 system were 0.725, 0.01, 0.14 and 0.125, respectively. The genotype frequencies were found to be 0.91 for the rapid acetylator and 0.09 for the slow acetylator. No significant differences were found in the hepatocellular carcinoma group. CONCLUSION: The distribution of CYP2D6 and NAT2 polymorphism is very unique in the Korean population, as characterized by the extremely low frequency of CYP2D6 poor-metabolizer and NAT2 slow acetylator. CYP2D6 and NAT2 polymorphisms did not seem to play an important role in the hepatic carcinogenesis in the Korean population.

Relationship between polymorphism of N-acetyltransferase 2 gene and susceptibility to bladder cancer / 中华泌尿外科杂志

Objective To investigate the relationship between genetic polymorphism of N-acetyltransferase 2(NAT2) and susceptibility to bladder cancer.Methods Based on case-control study,NAT2 mutation alleles(NAT2*5,*6 and*7) were determined by ASPCR and PCR-RFLP in 78 patients with bladder cancer and 80 nontumorous patients.In addtion,the relationships between the genotypes and tobacco smoking,occupational exposure,high dose intake of meat or pathological characteristic of bladder cancer patients were analyzed.Results In the blood samples from 158 cases,the 4 alleles NAT2*4,NAT2*5,NAT2*6 and NAT2*7 were detected.The frequency of NAT2 slow genotypes was 29.5%(23/78) in patients with bladder cancer,which was significantly higher compared with 16.3%(13/80) in control patients(P

Effects of Environmental Carcinogens and Genetic Polymorphisms of CYP2E1 and NAT2 on Gastric Carcinogenesis

PURPOSE: This study was performed to investigate the effects of environmental factors, genetic polymor phisms of cytochrome P450 2E1 (CYP2E1) and N-acetyltransferase 2 (NAT2), and their interactions on mutations of p53 and Ki-ras genes in Korean stomach cancer. METHODS: One hundred nine stomach cancer patients and 211 age- and sex-matched controls were enrolled in this study. Direct interview with a structured questionnaire was performed to get informations on the level of exposure to environmental factors. For genotyping of the metabolic enzymes, PCR-RFLP methods were used. RT-PCR and direct sequencing were carried out to detect mutations in the p53 and the Ki-ras genes of stomach cancer tissue. To evaluate the risk of stomach cancer, we calculated odds ratios for environmental and genetic factors, and their combinations. RESULTS: Past medical histories of gastritis, diabetes and asthma allergic rhinitis were significant risk factors for stomach cancer. Fried potatoes, squid and octopus, welsh onions and chestnuts and gingkonuts had protective effects against stomach cancer. On the contrary, chicken, soybean paste stew, and soybean milk were significantly related to an increased stomach cancer risk. The NAT2 rapid acetylator turned out to be a marginally significant risk factor for gastric cancer. Mutations of the p53 and the Ki-ras genes were detected in 27.5% and 10.7% of stomach cancer tissues, respectively. Frizzled rice, potato, beef, lard, pickled fish, chicken stew, anchovies, tempura, Welsh onions, eggs, bean-curd, Qing-style soybean paste stew, and ice cream were protective against p53 mutation whereas yogurt was a risk factor for p53 mutation in stomach cancer tissue. Ki-ras mutation was associated with less intake of pears and persimmons, melons, strawberries, grapes and milk and with more intake ofsoybean paste stew. In a multiple logistic analysis including genetic polymorphism, past medical history and diet intake, past history of gastritis, chicken, soybean paste stew, and soybean milk were significant risk factors for stomach cancer whereas past history of diabetes, squid and octopus, and Welsh onions were protective factors against stomach cancer. CONCLUSION: These results suggest that past medical history and diet are more important risk factors for stomach cancer than genetic polymorphism and that mutations of the p53 and the Ki-ras genes would be induced by the respective risk factors.

Occurrence and Specific Type of p53 and H-ras Mutations Based on Polymorphisms of NAT2 and GSTM1 in Human Bladder Cancer / 대한비뇨기과학회지

PURPOSE: Cancer development depends on not only activation of oncogene or inactivation of tumor suppressor gene but also activities of enzymes involved in the metabolism of various carcinogenic xenobiotics, such as arylamine N-acetyltrasferase 2(NAT 2) and glutathione S-transferase (GSTM1). We analyzed whether genetic polymorphisms of NAT2 and GSTM1 were correlated with the mutation patterns of p53 and H-ras genes in bladder tumor tissues. MATERIALS AND METHODS: In 49 bladder cancer patients, we performed direct DNA sequencing for the detection of mutations of p53 and H-ras gene in bladder tumor tissues, and adopted PCR and PCR-RFLP techniques for the analysis of genetic polymorphisms of NAT2 and GSTM1 using patients` blood samples, respectively. RESULTS: In 18 cases, mutations in p53 were detected whereas 1 case carried two mutations; thus total of 19 mutations were detected. Sixteen of these were point mutations including 13 of transversions and 3 of transitions, and others were 1 of frameshift and 2 of microdeletions-insertions. Among 33 patients, H-ras mutations were detected in 5 cases with 2 of transitions and 3 of transversions. The frequencies of slow, intermediate, and rapid acetylator in NAT2 genotyping analysis, were 10.2%, 40.8%, and 49.0%, respectively, and GSTM1 deletions were observed in 73.5%. We could not find any significant correlations between NAT2 or GSTM1 polymorphisms and the occurence of p53(p=0.614, p=0.310) or H-ras(p=0.500, p=0.582) mutations. Also, no apparent associations were seen for specific type of p53 and H-ras mutations according to polymorphisms of NAT2(p=0.456, p=0.600) and GSTM1(p=0.378, p=0.400). CONCLUSIONS: The polymorphisms of NAT2 and GSTM1, conjugating enzymes of foreign compound metabolism, were not considered to influence occurrence and type of mutations in p53 and H-ras in human bladder cancer.