Rapid Acetylators Research Articles

Rapid and intermediate N-acetylators are less susceptible to oxidative damage among 4,4′-methylenebis(2-chloroaniline) (MBOCA)-exposed workers

In this study, we explored the association between a marker of oxidative stress, 8-hydroxydeoxyguanosine (8-OHdG), and genetic polymorphism of the carcinogen-metabolizing enzyme N-acetyltransferase 2 (NAT2) among 4,4'-methylenebis(2-chloroaniline) (MBOCA)-exposed workers. The study population was recruited from four MBOCA-producing factories, and included 57 MBOCA-exposed workers and 101 unexposed control workers. Personal characteristics were collected by questionnaire. Plasma 8-OHdG levels were measured by LC/MS/MS. NAT2 alleles were measured by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). NAT2 polymorphism influenced the plasma 8-OHdG levels of MBOCA-exposed workers, but not of non-exposed workers. No difference between exposed and control groups was found for the crude 8-OHdG levels among rapid, intermediate, and slow acetylators. After adjusting for gender, age, smoking, and alcohol consumption habit, the 8-OHdG concentration in the MBOCA-exposed workers was 0.18pg/ml (95% CI -1.80 to -0.12) lower than the control group among rapid and intermediate acetylators. However, the difference between exposed and control groups was not significant for slow acetylators. Gene-environment interactions could play a role in the carcinogenesis of occupational MBOCA exposure. We suggest that the impact of the NAT2 acetylator status is low, if at all, on the generation of the oxidative stress marker 8-OHdG in the investigated exposed group.

Genetic Variation in Prediction of Drug Efficacy and Toxicity

Personalized medicine is currently transitioning from its maturation into the clinical practice [1]. The individual response difference to the drug is attributable to the pharmacogenomics make up of each individual, or to the pharmacokinetic difference in its ADME property as absorption, distribution, metabolism and excretion. The pharmacogenomics make up and genetic variation can be categorized into single nucleotide polymorphisms (SNPs), insertion, deletion, translocation or duplication of the genome sequence. Extensive work has been carried out to test the effect of gene SNPs on the drug disposition, efficacy or toxicity of the drug, and there are successful examples in the drug regulation in terms of appreciable pharmacogenomics on the drug dosage and effect. For example, the United States Food and Drug Administration (FDA) has modified the dosage of irinotecan in the population of homozygous UGT1A1*28 allele with reduced UGT1A1 activity. The patients’ plasma concentration of isoniazid which is an anti-tuberculosis drug had a bimodal distribution pattern. The difference in genomic make up of N-acetyltransferase gene differentiated the population into rapid vs. slow acetylators. The slow acetylators had higher isoniazid drug concentration, and the rapid acetylators had lower plasma drug concentration which in turn leads to diverse response/toxicity in these different populations [2].

Full-Gene-Sequencing Analysis ofN-Acetyltransferase-2 in an Adult Indian Population

Drug-metabolizing enzymes play a major role in determining the outcome of drug therapy. N-acetyltransferase-2 (NAT2) is one of the main enzymes involved in metabolism of isoniazid used in treatment of tuberculosis (TB). Several variations in the NAT2 gene give rise to multiple haplotypes that phenotypically code for different acetylator status. The objective was to generate a more unambiguous picture of the NAT2 scenario in India as compared to that obtained from polymerase chain reaction-restriction fragment length polymorphism methods. Full-gene-sequencing analysis of NAT2 was carried out in 181 healthy Indian subjects from different regional groups. A total of 33 diplotypes were recorded from six known single-nucleotide polymorphisms. The overall frequency of the slow acetylator haplotypes detected in this study was 65%, followed by 26% and 9% intermediate and rapid acetylators, respectively. Of the slow acetylator alleles, the NAT2*5B/*6A occurred in 25% of the study subjects. The study indicates that the frequency of slow acetylator alleles is high in the adult Indian population. Since the prevalence of TB is high in this population, pharmacogenetic testing for NAT2 alleles may be advisable before start of therapy with isoniazid to prevent drug toxicity.

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

ObjectiveThis study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis.MethodsIn a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week.ResultsOne hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen.ConclusionOur results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.

Study of NAT2 genetic polymorphism in West African subjects: example of an healthy non-smoker Senegalese population

The NAT2 genetic polymorphism determines the individual acetylator status and, consequently, the capacity to metabolize, or not, drugs and xenobiotics which are substrates of NAT2. As the nature and frequency of the NAT2 polymorphisms vary remarkably between populations of different ethnic origins, genotyping strategies used to predict the acetylation phenotype need to be adapted for each particular population regarding their genetic backgrounds at this locus. As few data on the genetic polymorphism of NAT2 are available in the Senegalese population, we performed an extensive identification of NAT2 variants in 105 healthy non-smoker Senegalese subjects by direct PCR sequencing of the coding region. Eleven previously described SNPs were identified in this Senegalese population. Upon allele analysis, the four most frequent alleles were of the NAT2*5- (35.7 %), NAT2*6- (21.0 %), NAT2*12- (16.7 %) and NAT2*14- (10.0 %) type, the remaining alleles, including the wild-type NAT2*4, having each a frequency lower than 10 %. According to the observed genotypes, 51 and 50 subjects were predicted to be of the rapid (48.6 %) and slow (47.6 %) acetylator phenotype, respectively, while four individuals (3.8 %) were considered of unknown phenotype as they carry at least one allele with a yet unknown functional effect. These baseline data would be of particular interest to set up an efficient genotyping strategy to predict the acetylation status of Senegalese patients with tuberculosis and, thus, to optimize their isoniazid treatment.

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population

Arylamine N-acetyltransferase-2 (NAT-2) is a key human enzyme in drug detoxification and elimination. Mutations in NAT-2 affect the activity of anti-tuberculosis drugs and result in three different phenotypes: rapid (RA), intermediate (IA) and slow acetylators (SA). The allelic, genotypic and phenotypic frequencies of NAT-2 were studied in 185 patients from Buenos Aires by restriction fragment length polymorphism. The following allele frequencies were obtained: *4 = 29.9%, *5 = 37.0, *6 = 25.6%, *7 = 8% and *14 = 1.3%. With regard to the phenotype, we observed that 53.6% of the population was SA, 35.7% was IA and 10.7% was RA. A high prevalence of SA might have an impact on anti-TB drug-induced hepatotoxicity.

NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population

Background. Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti-tuberculosis (TB) treatment. Some researchers suggested that determination of N-acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. Aim. To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population.Material and methods. A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values.Results. A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. Conclusions. In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients.

Pharmacokinetic/pharmacodynamic parameters and the choice of high-dosage rifamycins

Clinical trials and the behaviour of bacterial persisters. To explain why the efficacies of isoniazid (INH) and rifamycins during the treatment of tuberculosis (TB) are related not to the area under the curve (AUC)/minimum inhibitory concentration (MIC), but to peak drug concentrations. We examined the response in clinical trials with patients treated with INH alone and divided into slow and rapid acetylators of INH. The efficacy of INH is best related to peak concentrations, as repeated peaks can kill low-degree resistant mutants. A similar process might result in repeated peak concentrations of rifamycins killing low-tolerance persisters. If the efficacy of rifamycins is best related to peak concentrations, we can explain the discrepancy between mouse studies on daily rifapentine (RPT) and the failure to accelerate elimination of TB from sputum in the TBTC Study 29A, as daily RPT greatly increases the AUC but not the peak concentrations. High dosage rifampicin may be better able than RPT to cause high peaks.

NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug‐induced hepatotoxicity in Chinese patients

1. The present study investigated the relationship between antituberculosis (anti-TB) drug-induced hepatotoxicity and genetic polymorphisms of two important drug-metabolizing enzymes involved in the metabolism of isoniazid, namely N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1). 2. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 and CYP2E1 genes in tuberculosis (TB) patients with (n = 101) or without (n = 107) anti-TB drug-induced hepatotoxicity. Associations between various genetic polymorphisms and anti-TB drug-induced hepatotoxicity were then determined. 3. Patients with NAT2 (282TT , 590AA and 857GA) alleles had an increased susceptibility to anti-TB drug-induced hepatotoxicity. The slow acetylator NAT2 genotypes (especially NAT2*6A/7B and NAT2*6A/6A) were risk factors for hepatotoxicity (odds ratio (OR) 9.57 (P < 0.001) for NAT2*6A/7B; OR 5.24 (P = 0.02) for NAT2*6A/6A). 4. The CYP2E1 genotype per se was not significantly associated with the development of anti-TB drug-induced hepatotoxicity. However, the combination of the CYP2E1 C1/C1 genotype with a slow acetylator NAT2 genotype increased the risk of anti-TB drug-induced hepatotoxicity (OR 5.33; P = 0.003) compared with the combination of a rapid acetylator NAT2 genotype with either a C1/C2 or C2/C2 genotype. 5. Thus, slow acetylators with the NAT2*6A/7B and NAT2*6A/6A genotypes combined with the C1/C1 CYP2E1 genotype may be involved in the pathogenesis of anti-TB drug-induced hepatotoxicity. 6. The present findings may be explained, in part, by changes in the metabolism of the anti-TB drug isoniazid induced via NAT2 and CYP2E1, a metabolic process known to produce hepatotoxic intermediates.

Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy

Using hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators. Thirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI, .9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or small-study effects were observed for the outcomes evaluated. Pharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.

Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study

BackgroundThere are no known causes for progressive supranuclear palsy (PSP). The microtubule associated protein tau (MAPT) H1 haplotype is the major genetic factor associated with risk of PSP, with both oxidative stress and mitochondrial dysfunction also implicated. We investigated whether specific single nucleotide polymorphisms (SNPs) in genes encoding enzymes of xenobiotic detoxification, mitochondrial functioning, or oxidative stress response, including debrisoquine 4-hydroxylase, paraoxonase 1 and 2, N-acetyltransferase 1 and 2 (NAT2), superoxide dismutase 1 and 2, and PTEN-induced putative kinase are associated with PSP.MethodsDNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay.ResultsThe proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001).ConclusionsOur results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.

NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis [Review article

Although a series of studies have evaluated the potential association between N-acetyltransferase 2 (NAT2) polymorphisms and the risk of anti-tuberculosis drug-induced liver injury (ATLI), the results have generally been controversial and inadequate, mainly due to limited power. The present meta-analysis sought to resolve this problem. PubMed, Embase and Web of Science were searched using the following key words: 'N-acetyltransferase 2' or 'NAT2' and 'polymorphism' and 'tuberculosis' or 'TB' and 'hepatotoxicity' or 'liver injury'. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were summarised in forest plots and set out in a table. A total of 14 studies, comprising 474 cases and 1446 controls, were included in the meta-analysis. A significant association was observed between NAT2 slow acetylators and the risk of ATLI. The OR for NAT2 slow acetylators compared with rapid acetylators was 4.697 (95%CI 3.291-6.705, P < 0.001). Subgroup analyses indicate that both Asian and non-Asian cases with slow acetylators develop ATLI more frequently, which is similar to patients with slow acetylators receiving first-line combination treatment. On comparing NAT2 intermediate acetylators with rapid acetylators, the OR for ATLI was 1.261 (95%CI 0.928-1.712, P = 0.138). This meta-analysis showed that tuberculosis patients with slow acetylators had a higher risk of ATLI than other acetylators. Screening of patients for the NAT2 genetic polymorphisms will be useful for the clinical prediction and prevention of ATLI.

A Meta-Analysis of the Relationship Between NAT 2 Polymorphism and Colorectal Cancer Susceptibility

Background and Objective. Although the association between N-acetyltransferase 2 (NAT2) polymorphism and colorectal cancer (CRC) susceptibility in humans has been extensively investigated, the results are contradictory. The aim of this study was to conduct a meta-analysis of published studies to quantitatively summarize the association between NAT2 polymorphism and risk of CRC. Material and Methods. Relevant studies that had investigated NAT2 polymorphism and CRC susceptibility were identified through a comprehensive search of Pubmed, EMBASE, Medline, Biosis, Wiley-Blackwell, ISI Web of Knowledge, CNKI, and Chinese Biomedicine Database until October 2011. After selection based on the inclusion and exclusion criteria, the relevant data were extracted from each study, and finally a meta-analysis was performed. Results. Eight phenotype studies (791 cases and 1158 controls) and 45 genotype studies (13 875 cases and 18 879 controls) were included in the present meta-analysis. The pooling of phenotype studies showed no significant association between the NAT2 acetylator status and CRC susceptibility (rapid acetylator, OR, 1.32; 95% CI, 0.92–1.89, P=0.14; slow acetylator, OR, 0.76; 95% CI, 0.53–1.09, P=0.14). The combined ORs for rapid and slow acetylator status and CRC risk in genotype studies were 1.01 (95% CI, 0.94–1.08; P=0.86) and 0.99 (95% CI, 0.93–1.06; P=0.86), respectively. In the subgroup analysis by regions, no increased risks were found in Asians, Europeans, Americans, or Australasians. Pooling studies were also conducted on the groups of gender, specific tumor sites, and smoking status, but no significant association in genotype distribution between CRC and control was found as well. Conclusions. These results of our meta-analysis suggest that there is no overall association between NAT2 polymorphism and CRC susceptibility.

Single-Dose Tolerability, Pharmacokinetics, and Pharmacodynamics of Etamicastat (BIA 5-453), a New Dopamine β-Hydroxylase Inhibitor, in Healthy Subjects

The safety, tolerability, pharmacokinetics, and pharmacodynamics of etamicastat (BIA 5-453), a novel dopamine β-hydroxylase (DβH) inhibitor, were investigated in 10 sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. In each group, 6 subjects received a single dose of etamicastat (2, 10, 20, 50, 100, 200, 400, 600, 900, or 1200 mg) and 2 subjects received placebo. Etamicastat was well tolerated at all dose levels tested. Maximum plasma etamicastat concentrations occurred at 1 to 3 hours postdose. Elimination was biphasic, characterized by a first short early elimination half-life followed by a longer elimination phase of 16 to 20 hours for etamicastat doses of 100 mg and above. A high interindividual variability of pharmacokinetic parameters of etamicastat and its acetylated metabolite was observed. Pharmacogenomic data showed that N-acetyltransferase type 2 (NAT2) phenotype (rapid or slow N-acetylating ability) was a major source of variability. In NAT2 poor acetylators, the area under the plasma concentration-time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t ) of etamicastat was twice that observed in rapid acetylators. Consistent with that finding, AUC0-t of the acetylated metabolite was markedly higher in NAT2 rapid acetylators compared with poor acetylators. Inhibition of DβH activity was observed, reaching statistical significance for etamicastat doses of 100 mg and above.

Polymorphisms of arylamine N-acetyltransferase2 and risk of lung and colorectal cancer

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.

Accuracy of Various Human NAT2 SNP Genotyping Panels to Infer Rapid, Intermediate and Slow Acetylator Phenotypes

Humans exhibit genetic polymorphism in NAT2 resulting in rapid, intermediate and slow acetylator phenotypes. Over 65 NAT2 variants possessing one or more SNPs in the 870-bp NAT2 coding region have been reported. The seven most frequent SNPs are rs1801279 (191G>A), rs1041983 (282C>T), rs1801280 (341T>C), rs1799929 (481C>T), rs1799930 (590G>A), rs1208 (803A>G) and rs1799931 (857G>A). The majority of studies investigate the NAT2 genotype assay for three SNPs: 481C>T, 590G>A and 857G>A. A tag-SNP (rs1495741) recently identified in a genome-wide association study has also been proposed as a biomarker for the NAT2 phenotype. Sulfamethazine N-acetyltransferase catalytic activities were measured in cryopreserved human hepatocytes from a convenience sample of individuals in the USA with an ethnic frequency similar to the 2010 US population census. These activities were segregated by the tag-SNP rs1495741 and each of the seven SNPs described above. We assessed the accuracy of the tag-SNP and various two-, three-, four- and seven-SNP genotyping panels for their ability to accurately infer NAT2 phenotype. The accuracy of the various NAT2 SNP genotype panels to infer NAT2 phenotype were as follows: seven-SNP: 98.4%; tag-SNP: 77.7%; two-SNP: 96.1%; three-SNP: 92.2%; and four-SNP: 98.4%. A NAT2 four-SNP genotype panel of rs1801279 (191G>A), rs1801280 (341T>C), rs1799930 (590G>A) and rs1799931 (857G>A) infers NAT2 acetylator phenotype with high accuracy, and is recommended over the tag-, two-, three- and (for economy of scale) the seven-SNP genotyping panels, particularly in populations of non-European ancestry.

Association of NAT2 phenotype with risk of head and neck carcinoma: A meta-analysis

N-acetyltransferase 2 (NAT2) is a key enzyme involved in the metabolism of xenobiotics and plays a significant role in the detoxification of numerous potential carcinogens. According to its acetylation status, NAT2 acetylator may be classified into two phenotypes, rapid and slow. Numerous studies have demonstrated that the polymorphisms of NAT2 were correlated with individual susceptibility to several malignant neoplasms, including head and neck carcinomas (HNC). However, the associations between the acetylator phenotypes and HNC risk in each study were not entirely consistent. To assess these associations more comprehensively, we performed a meta-analysis. In this meta-analysis, 16 eligible studies including 2,965 cases with HNC and 3,919 controls were identified by searching the databases of PubMed, Medline and the ISI Web of Knowledge. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to evaluate the association. No significant associations between the rapid acetylator phenotype in NAT2 and HNC risk were found either in the overall analysis (OR=0.98; 95% CI 0.83, 1.15; I(2)=57%; P(heterogeneity)=0.003) or in the subgroup analysis by ethnicity (for the Caucasian population, OR=1.03, 95% CI 0.85, 1.24, I(2)=63%, P(heterogeneity)=0.002; for other mixed populations, OR=0.78, 95% CI=0.61, 1.00, I(2)=0%, P(heterogeneity)=0.47). In conclusion, this meta-analysis suggested that there is no association between the NAT2 phenotype and the risk of HNC.

Human N-acetyltransferase 1 *10 and *11 alleles increase protein expression through distinct mechanisms and associate with sulfamethoxazole-induced hypersensitivity

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 with wild-type NAT1 *4 and to confer cancer risk, through 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 was discovered in this study), B lymphocytes, and transfected cells. In a clinical study of 469 patients with HIV/AIDS 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'-untranslated region (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'-untranslated region 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 individuals who are 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 seems to protect against SMX toxicity by compensating for slow NAT2 acetylator status.

Possible association of NAT2 polymorphism with laryngeal cancer risk: an evidence-based meta-analysis

N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of various potential carcinogens, which can be subdivided into rapid and slow acetylation phenotype according to the different genotypes. A number of studies have been devoted to the association of NAT2 polymorphism with susceptibility to laryngeal carcinoma; however, the results were inconsistent and inconclusive. The aim of the present study was to conduct a meta-analysis assessing the possible association of NAT2 polymorphism with laryngeal cancer risk. The relevant studies were identified through a search of PubMed, Embase, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure until February 2011 and selected on the basis of the established inclusion criteria for publications, and then a meta-analysis was performed to quantitatively summarize the association of NAT2 polymorphism with laryngeal cancer susceptibility. Seven studies were included in the present meta-analysis, which described a total of 980 laryngeal cancer cases and 1,487 controls. The overall odds ratio (OR) for NAT2 slow and rapid acetylators was 0.99 (95% CI = 0.71-1.38) and 1.01 (95% CI = 0.72-1.40), respectively. When stratifying for race, the pooled ORs for NAT2 slow acetylator were 1.99 (95% CI = 1.10-3.63) in Asians and 0.85 (95% CI = 0.62-1.15) in Caucasians, and the pooled ORs for NAT2 rapid acetylator were 0.50 (95% CI = 0.28-0.91) in Asians and 1.18 (95% CI = 0.87-1.60) in Caucasians. This meta-analysis suggested that there was overall lack of association between NAT2 polymorphism and laryngeal cancer risk; however, NAT2 slow acetylation may contribute to a risk factor for laryngeal cancer in Asians but not in Caucasians.

N-acetyltransferase-2 (NAT2) Gene Polymorphisms and Enzyme Activity in Serbs: Unprecedented High Prevalence of Rapid Acetylators in a White Population

The aim of this study was to investigate N-acetyltransferase 2 (NAT2) genetic polymorphism and enzyme activity in Serbs, and to examine the influence of NAT2 genotype, sex, and smoking on the phenotype. Genotyping for 190C>T, 282C>T, 341T>C, 403C>G, 411T>A, 481C>T, 590G>A, 803A>G, and 857G>A in the NAT2 gene, was performed in 140 healthy Serbs. NAT2 activity was determined as AFMU/ (AFMU + 1X + 1U) urinary ratio in 100 subjects using caffeine as a probe. The most frequent NAT2 haplotypes were NAT2*5B (38.2%), NAT2*6A (26.0%), and NAT2*4 (24.4%). The log-transformed NAT2 activity indices exhibited trimodal distribution with 9%, 36%, and 55% of slow, intermediate, and rapid acetylators, respectively. Significant NAT2 genotype-phenotype correlation was observed (P < .0001). The frequency of NAT1*10 and NAT1*11 were 27.5% and 6.9%, respectively. There was no significant influence of sex or cigarette smoking on NAT2 enzyme activity. Eight subjects displayed rapid NAT2 acetylators phenotype despite being homozygous for NAT2 slow alleles, and NAT1 fast acetylators genotype (NAT1*10 and NAT1*11) had no implication. In contrast to other white populations described hitherto, rapid acetylator is the predominant NAT2 phenotype in Serbs. NAT2 genotype, but not sex and cigarette smoking, influence enzyme activity. NAT1 fast acetylators genotypes do not contribute for NAT2 genotype-phenotype discordance.