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Antony Payton - One of the best experts on this subject based on the ideXlab platform.
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No association between apolipoprotein E or N-Acetyltransferase 2 gene polymorphisms and age-related hearing loss
Laryngoscope, 2014Co-Authors: Piers Dawes, Hazel Platt, M A Horan, William E R Ollier, Kevin J. Munro, Neil Pendleton, Antony PaytonAbstract:OBJECTIVES/HYPOTHESIS: Age-related hearing loss has a genetic component, but there have been limited genetic studies in this field. Both N-Acetyltransferase 2 and apolipoprotein E genes have previously been associated. However, these studies have either used small sample sizes, examined a limited number of polymorphisms, or have produced conflicting results. Here we use a haplotype tagging approach to determine association with age-related hearing loss and investigate epistasis between these two genes. STUDY DESIGN: Candidate gene association study of a continuous phenotype. METHODS: We investigated haplotype tagging single nucleotide polymorphisms in the N-Acetyltransferase 2 gene and the presence/absence of the apolipoprotein E ?4 allele for association with age-related hearing loss in a cohort of 265 Caucasian elderly volunteers from Greater Manchester, United Kingdom. Hearing phenotypes were generated using principal component analysis of the hearing threshold levels for the better ear (severity, slope, and concavity). Genotype data for the N-Acetyltransferase 2 gene was obtained from existing genome-wide association study data from the Illumina 610-Quadv1 chip. Apolipoprotein E genotyping was performed using Sequenom technology. Linear regression analysis was performed using Plink and Stata software. RESULTS: No significant associations (P value,?>?0.05) were observed between the N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms and any hearing factor. No significant association was observed for epistasis analysis of apolipoprotein E ?4 and the N-Acetyltransferase 2 single nucleotide polymorphism rs1799930 (NAT2*6A). CONCLUSION: We found no evidence to support that either N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms are associated with age-related hearing loss in a cohort of 265 elderly volunteers. LEVEL OF EVIDENCE: N/A. Laryngoscope, 2014.
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No association between apolipoprotein E or N-Acetyltransferase 2 gene polymorphisms and age-related hearing loss.
The Laryngoscope, 2014Co-Authors: Piers Dawes, Hazel Platt, Neil Pendleton, Michael Horan, William Ollier, Kevin Munro, Antony PaytonAbstract:Age-related hearing loss has a genetic component, but there have been limited genetic studies in this field. Both N-Acetyltransferase 2 and apolipoprotein E genes have previously been associated. However, these studies have either used small sample sizes, examined a limited number of polymorphisms, or have produced conflicting results. Here we use a haplotype tagging approach to determine association with age-related hearing loss and investigate epistasis between these two genes. Candidate gene association study of a continuous phenotype. We investigated haplotype tagging single nucleotide polymorphisms in the N-Acetyltransferase 2 gene and the presence/absence of the apolipoprotein E ε4 allele for association with age-related hearing loss in a cohort of 265 Caucasian elderly volunteers from Greater Manchester, United Kingdom. Hearing phenotypes were generated using principal component analysis of the hearing threshold levels for the better ear (severity, slope, and concavity). Genotype data for the N-Acetyltransferase 2 gene was obtained from existing genome-wide association study data from the Illumina 610-Quadv1 chip. Apolipoprotein E genotyping was performed using Sequenom technology. Linear regression analysis was performed using Plink and Stata software. No significant associations (P value, > 0.05) were observed between the N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms and any hearing factor. No significant association was observed for epistasis analysis of apolipoprotein E ε4 and the N-Acetyltransferase 2 single nucleotide polymorphism rs1799930 (NAT2*6A). We found no evidence to support that either N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms are associated with age-related hearing loss in a cohort of 265 elderly volunteers. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.
David W. Hein - One of the best experts on this subject based on the ideXlab platform.
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Arylamine N-Acetyltransferase 2 genotype-dependent N-acetylation of isoniazid in cryopreserved human hepatocytes.
Acta pharmaceutica Sinica. B, 2017Co-Authors: Mark A. Doll, Raúl A. Salazar-gonzález, Srineil Bodduluri, David W. HeinAbstract:Cryopreserved human hepatocytes were used to investigate the role of arylamine N-Acetyltransferase 2 (NAT2; EC 2.3.1.5) polymorphism on the N-acetylation of isoniazid (INH). NAT2 genotype was determined by Taqman allelic discrimination assay and INH N-acetylation was measured by high performance liquid chromatography. INH N-acetylation rates in vitro exhibited a robust and highly significant (P
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Functional Characterization of Single Nucleotide Polymorphisms and Haplotypes of Human N-Acetyltransferase 2
Carcinogenesis, 2007Co-Authors: Yu Zang, Mark A. Doll, Shuang Zhao, J. Christopher States, David W. HeinAbstract:Human N-Acetyltransferase 2 (NAT2) is polymorphic in humans and may associate with cancer risk by modifying individual susceptibility to cancers from carcinogen exposure. Since molecular epidemiological studies investigating these associations usually include determining NAT2 single-nucleotide polymorphisms (SNPs), haplotypes or genotypes, their conclusions can be compromised by the uncertainty of genotype-phenotype relationships. We characterized NAT2 SNPs and haplotypes by cloning and expressing recombinant NAT2 allozymes in mammalian cells. The reference and variant recombinant NAT2 allozymes were characterized for arylamine N-acetylation and O-acetylation of N-hydroxy-arylamines. SNPs and haplotypes that conferred reduced enzymatic activity did so by reducing NAT2 protein without changing NAT2 mRNA levels. Among SNPs that reduced catalytic activity, G191A (R64Q), G590A (R197Q) and G857A (G286E) reduced protein half-life but T341C (I114T), G499A (E167K) and A411T (L137F) did not. G857A (G286E) and the major haplotype possessing this SNP (NAT2 * 7B) altered the affinity to both substrate and cofactor acetyl coenzyme A, resulting in reduced catalytic activity toward some substrates but not others. Our results suggest that coding region SNPs confer slow acetylator phenotype by multiple mechanisms that also may vary with arylamine exposures.
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Metabolic Activation of 2-Hydroxyamino-1-methyl-6- phenylimidazo(4,5-b)pyridine in Syrian Hamsters Congenic at the N-Acetyltransferase 2 (NAT2) Locus
Toxicological sciences : an official journal of the Society of Toxicology, 2003Co-Authors: Adrian J. Fretland, Mark A. Doll, Shuang Zhao, Uday S. Devanaboyina, Gong H. Xiao, David W. HeinAbstract:2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen prevalent in the human diet. To exert its mutagenic and carcinogenic effects, PhIP undergoes bioactivation to N-hydroxy-PhIP followed by O-esterification via cytosolic acetyltransferases or sulfotransferases to form DNA adducts. We investigated the role of cytosolic acetyltransferases and sulfotransferases and the role of the N-Acetyltransferase 2 genetic polymorphism on PhIP DNA-adduct levels in a congenic Syrian hamster model. DNA adduct levels were detected in all hepatic and extrahepatic tissues tested following administration of PhIP (4 100 mg/kg) or Nhydroxy-PhIP (1 50 mg/kg), with the highest levels in pancreas. DNA-adduct levels were higher in the gastrointestinal tract of rapid and slow acetylator hamsters administered N-hydroxy-PhIP. N-hydroxy-PhIP O-acetyltransferase and O-sulfotransferase activities were detected in most hepatic and extrahepatic cytosols derived from rapid and slow acetylator congenic hamsters. N-hydroxy-PhIP Oacetyltransferase activity was significantly higher (p < 0.05) in liver, small intestine, and esophagus in rapid than in slow acetylator congenic hamsters. N-hydroxy-PhIP O-acetyltransferase activities correlated significantly with N-Acetyltransferase 2 activities across tissues in rapid (r 0.83; p 0.0004) but not in slow (r 0.46; p 0.1142) acetylator congenic hamsters, suggesting catalysis primarily by NAT2 in rapid acetylators but NAT1 in slow acetylators. N-hydroxy
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Functional genomics of C190T single nucleotide polymorphism in human N-Acetyltransferase 2.
Biological chemistry, 2002Co-Authors: Yuanqi Zhu, Mark A. Doll, David W. HeinAbstract:N-Acetyltransferase 2 (NAT2) catalyzes N-acetylation and O-acetylation of many drugs and environmental carcinogens. Genetic polymorphisms in the NAT2 gene have been associated with differential susceptibility to cancers and drug toxicity from these compounds. Single nucleotide polymorphisms (SNPs) have been identified in the human NAT2 coding region. A new allele, NAT2*19, possessing the C 1 9 0 T (R 6 4 W) exchange, was recently identified. In order to understand the effect of this new SNP, recombinant NAT2*4 (reference) and NAT2*19 were expressed in yeast (Schizosaccharomyces pombe). The C 1 9 0 T (R 6 4 W) SNP in NAT2*19 caused substantial reduction in the NAT2 protein level and stability, but did not cause significant reduction in transformation efficiency or mRNA level. The enzymatic activities for N-acetylation of two arylamine carcinogens (2-aminofluorene, 4-aminobiphenyl), and a sulfonamide drug (sulfamethazine) were over 100-fold lower for NAT2 19 compared to reference NAT2 4. Kinetic studies showed a reduction in V m a x but no significant change in substrate K m . In addition, the SNP caused significant reduction in the O-acetylation of the N-hydroxy-2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine. These results show that NAT2*19 possessing the C 1 9 0 T (R 6 4 W) SNP encodes a slow acetylator phenotype for both N- and O-acetylation, due to a reduction in the amount and stability of the NAT2 19 allozyme.
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Functional characterization of human N-Acetyltransferase 2 (NAT2) single nucleotide polymorphisms.
Pharmacogenetics, 2001Co-Authors: Adrian J. Fretland, Matthew A. Leff, Mark A. Doll, David W. HeinAbstract:N-Acetyltransferase 2 (NAT2) catalyses the activation and/or deactivation of a variety of aromatic amine drugs and carcinogens. Polymorphisms in the N-Acetyltransferase 2 (NAT2) gene have been associated with a variety of drug-induced toxicities, as well as cancer in various tissues. Eleven single nucleotide polymorphisms (SNPs) have been identified in the NAT2 coding region, but the specific effects of each of these SNPs on expression of NAT2 protein and N-Acetyltransferase enzymatic activity are poorly understood. To investigate the functional consequences of SNPs in the NAT2 coding region, reference NAT2*4 and NAT2 variant alleles possessing one of the 11 SNPs in the NAT2 coding region were cloned and expressed in yeast (Schizosaccharomyces pombe). Reductions in catalytic activity for the N-acetylation of a sulfonamide drug (sulfamethazine) and an aromatic amine carcinogen (2-aminofluorene) were observed for NAT2 variants possessing G191A (R64Q), T341C (I114T), A434C (E145P), G590A (R197Q), A845C (K282T) or G857A (G286T). Reductions in expression of NAT2 immunoreactive protein were observed for NAT2 variants possessing T341C, A434C or G590A. Reductions in protein stability were noted for NAT2 variants possessing G191A, A845C, G857A or, to some extent, G590A. No significant differences in mRNA expression or transformation efficiency were observed among any of the NAT2 alleles. These results suggest two mechanisms for slow acetylator phenotype(s) and more clearly define the effects of individual SNPs on human NAT2 expression, stability and catalytic activity.
Piers Dawes - One of the best experts on this subject based on the ideXlab platform.
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No association between apolipoprotein E or N-Acetyltransferase 2 gene polymorphisms and age-related hearing loss
Laryngoscope, 2014Co-Authors: Piers Dawes, Hazel Platt, M A Horan, William E R Ollier, Kevin J. Munro, Neil Pendleton, Antony PaytonAbstract:OBJECTIVES/HYPOTHESIS: Age-related hearing loss has a genetic component, but there have been limited genetic studies in this field. Both N-Acetyltransferase 2 and apolipoprotein E genes have previously been associated. However, these studies have either used small sample sizes, examined a limited number of polymorphisms, or have produced conflicting results. Here we use a haplotype tagging approach to determine association with age-related hearing loss and investigate epistasis between these two genes. STUDY DESIGN: Candidate gene association study of a continuous phenotype. METHODS: We investigated haplotype tagging single nucleotide polymorphisms in the N-Acetyltransferase 2 gene and the presence/absence of the apolipoprotein E ?4 allele for association with age-related hearing loss in a cohort of 265 Caucasian elderly volunteers from Greater Manchester, United Kingdom. Hearing phenotypes were generated using principal component analysis of the hearing threshold levels for the better ear (severity, slope, and concavity). Genotype data for the N-Acetyltransferase 2 gene was obtained from existing genome-wide association study data from the Illumina 610-Quadv1 chip. Apolipoprotein E genotyping was performed using Sequenom technology. Linear regression analysis was performed using Plink and Stata software. RESULTS: No significant associations (P value,?>?0.05) were observed between the N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms and any hearing factor. No significant association was observed for epistasis analysis of apolipoprotein E ?4 and the N-Acetyltransferase 2 single nucleotide polymorphism rs1799930 (NAT2*6A). CONCLUSION: We found no evidence to support that either N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms are associated with age-related hearing loss in a cohort of 265 elderly volunteers. LEVEL OF EVIDENCE: N/A. Laryngoscope, 2014.
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No association between apolipoprotein E or N-Acetyltransferase 2 gene polymorphisms and age-related hearing loss.
The Laryngoscope, 2014Co-Authors: Piers Dawes, Hazel Platt, Neil Pendleton, Michael Horan, William Ollier, Kevin Munro, Antony PaytonAbstract:Age-related hearing loss has a genetic component, but there have been limited genetic studies in this field. Both N-Acetyltransferase 2 and apolipoprotein E genes have previously been associated. However, these studies have either used small sample sizes, examined a limited number of polymorphisms, or have produced conflicting results. Here we use a haplotype tagging approach to determine association with age-related hearing loss and investigate epistasis between these two genes. Candidate gene association study of a continuous phenotype. We investigated haplotype tagging single nucleotide polymorphisms in the N-Acetyltransferase 2 gene and the presence/absence of the apolipoprotein E ε4 allele for association with age-related hearing loss in a cohort of 265 Caucasian elderly volunteers from Greater Manchester, United Kingdom. Hearing phenotypes were generated using principal component analysis of the hearing threshold levels for the better ear (severity, slope, and concavity). Genotype data for the N-Acetyltransferase 2 gene was obtained from existing genome-wide association study data from the Illumina 610-Quadv1 chip. Apolipoprotein E genotyping was performed using Sequenom technology. Linear regression analysis was performed using Plink and Stata software. No significant associations (P value, > 0.05) were observed between the N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms and any hearing factor. No significant association was observed for epistasis analysis of apolipoprotein E ε4 and the N-Acetyltransferase 2 single nucleotide polymorphism rs1799930 (NAT2*6A). We found no evidence to support that either N-Acetyltransferase 2 or apolipoprotein E gene polymorphisms are associated with age-related hearing loss in a cohort of 265 elderly volunteers. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.
Markus Wenk - One of the best experts on this subject based on the ideXlab platform.
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Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N‐acetyltransferase 2, and xanthine oxidase in healthy males and females
British journal of clinical pharmacology, 2004Co-Authors: Markus Wenk, Liliane Todesco, Stephan KrähenbühlAbstract:Aims To investigate the influence of St. John's wort (SJW) on CYP3A4, CYP1A2, CYP2D6, N-Acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activities in healthy males and females.
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Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-Acetyltransferase 2 and CYP1A2 activities.
European journal of clinical pharmacology, 1999Co-Authors: P. Fuchs, Walter E. Haefeli, H. R. Ledermann, Markus WenkAbstract:Objectives: To evaluate the in vivo effect of xanthine oxidase (XO) inhibition by allopurinol on the determination of polymorphic N-Acetyltransferase 2 (NAT2) and cytochrome P450 1A2 (CYP1A2) with urinary caffeine metabolic ratios.
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Acetaminophen is an inhibitor of hepatic N-Acetyltransferase 2 in vitro and in vivo.
Pharmacogenetics, 1998Co-Authors: Jean-pierre Rothen, Walter E. Haefeli, Liliane Todesco, Urs A. Meyer, Markus WenkAbstract:Slow acetylators of the polymorphic N-Acetyltransferase 2 (NAT2, EC 2.3.1.5) suffer more often from side-effects of NAT-substrates than fast acetylators. Since concomitant administration of drugs may inhibit NAT2, we studied the influence of acetaminophen on NAT2 in human hepatic cytosol in vitro and in healthy individuals. In-vitro acetylation was assessed in liver homogenate of one fast and one slow acetylator using sulfamethazine as a test substrate. Acetaminophen competitively inhibited sulfamethazine acetylation in fast and slow acetylator liver samples with Ki values of acetaminophen of 2144 micromol/l and 712 micromol/l, respectively. In additional experiments, exposure of human liver cytosol to p-aminophenol, a putative precursor of acetaminophen in this reaction, revealed production of substantial amounts of acetaminophen, which indirectly suggests that acetaminophen may bind to the active site of NAT2. In-vivo acetylation was quantified with a urinary caffeine assay in 20 healthy volunteers at baseline and after repetitive oral administration of 1000 mg acetaminophen every 6 h for 1 day. The ratio of the acetylated caffeine metabolite acetyl-amino-6-formylamino-3-methyluracil to 1-methylxanthine was reduced by 30.9% (range 11.0-50.1%) in fast acetylators (n = 10) and by 19.3% (range 0.2-36.5%) in slow acetylators (n = 10). Acetaminophen, a widely used over-the-counter drug, which shares structural similarities with acetylated products, inhibits NAT2 both in vitro and in vivo. These findings suggest that even compounds which are not metabolized by NAT2 may inhibit the enzyme and reduce its metabolic capacity.
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N‐Acetyltransferase 2 polymorphism in patients infected with human immunodeficiency virus
Clinical pharmacology and therapeutics, 1996Co-Authors: Gilbert R. Kaufmann, Markus Wenk, Walter Taeschner, Bettina Peterli, K. Gyr, Urs A. Meyer, Walter E. HaefeliAbstract:Objectives To evaluate the prevalence of slow acetylation of hepatic N-Acetyltransferase 2 (NAT2) in patients with different stages of human immunodeficiency virus (HIV) infection, to assess the relationship between acetylation capacity and the degree of immunosuppression, and to study the concordance between NAT2 phenotype and genotype. Methods This prospective study in a consecutive sample of HIV-infected patients was performed in the outpatient department of a university hospital that provides primary and tertiary care. The NAT2 genotype was assessed by polymerase chain reaction and restriction fragment length polymorphism, the NAT2 phenotype was determined by caffeine test (urinary metabolic ratio of the caffeine metabolites 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine). Results Fifty patients with Centers for Disease Control HIV infection stages A (10 patients), B (20 patients), and C (20 patients) were included in the study after each gave informed consent. According to genotyping and phenotyping, 32 (64%) patients were slow acetylators, with a concordance of the two methods of 96%. The overall distribution was similar to distributions reported in other white populations. The slow acetylator phenotype was found in seven, 16, and nine patients with stage A, B, and C, respectively. Eight of the 10 patients with previous adverse reactions to sulfonamides had slow acetylator phenotypes. Acetylation capacity was independent of CD4 cell counts. Conclusions This study revealed an excellent agreement between genotypes and phenotypes of NAT2 in patients with HIV infection. There was no increase in prevalence of slow acetylation in patients with advanced stages of the disease. This apparent discrepancy to an earlier study may be the result of differences in co-medication of the patients studied and may point to the relevance of drug interactions in the treatment of patients with HIV infection. Clinical Pharmacology & Therapeutics (1996) 60, 62–67; doi:
Ali Akbar Velayati - One of the best experts on this subject based on the ideXlab platform.
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Arylamine N-Acetyltransferase 2 slow acetylator polymorphisms in unrelated Iranian individuals
European Journal of Clinical Pharmacology, 2004Co-Authors: Valery V. Bakayev, F Mohammadi, Moslem Bahadori, Mariam Sheikholslami, Arash Javeri, Mohammad Reza Masjedi, Ali Akbar VelayatiAbstract:Objective To determine the frequency of mutations at the polymorphic gene coding for arylamine N -acetyltransferase 2 (NAT2, EC 2.3.1.5) and NAT2 genotypes associated with slow acetylation in healthy Iranian individuals. Methods The polymorphisms in the NAT2 gene from 88 unrelated healthy subjects (48 men/40 women) from the general Tehran population were discriminated using polymerase chain reaction (PCR) with allele-specific primers (341 C>T) and PCR-restriction fragment length polymorphism analysis (481 C>T, 590 G>A, and 857 G>A). Results Frequencies of the studied polymorphisms showed the most common alleles to be NAT2*4 (0.43) and NAT2*5 , 481 C>T (0.32), followed by NAT2*6 (0.19) and NAT2*7 (0.06), previously referred to as WT, M1, M2, and M3, respectively. The most prevalent genotypes were NAT2*4/*5 [(31.8%; 95% confidence interval (CI): 29–34%] and *4/*4 (18.2%; 95% CI: 16–21%). When grouped according to the expected phenotypical effects, the resulting genotypes revealed the significant prevalence of the subjects with slow (32.9%) and intermediate (48.9%) acetylation status compared with wild-type rapid (18.2%) acetylators ( P
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Arylamine N-Acetyltransferase 2 slow acetylator polymorphisms in unrelated Iranian individuals
European Journal of Clinical Pharmacology, 2004Co-Authors: Valery V. Bakayev, F Mohammadi, Moslem Bahadori, Mariam Sheikholslami, Arash Javeri, Mohammad Reza Masjedi, Ali Akbar VelayatiAbstract:Objective To determine the frequency of mutations at the polymorphic gene coding for arylamine N -acetyltransferase 2 (NAT2, EC 2.3.1.5) and NAT2 genotypes associated with slow acetylation in healthy Iranian individuals. Methods The polymorphisms in the NAT2 gene from 88 unrelated healthy subjects (48 men/40 women) from the general Tehran population were discriminated using polymerase chain reaction (PCR) with allele-specific primers (341 C>T) and PCR-restriction fragment length polymorphism analysis (481 C>T, 590 G>A, and 857 G>A). Results Frequencies of the studied polymorphisms showed the most common alleles to be NAT2*4 (0.43) and NAT2*5 , 481 C>T (0.32), followed by NAT2*6 (0.19) and NAT2*7 (0.06), previously referred to as WT, M1, M2, and M3, respectively. The most prevalent genotypes were NAT2*4/*5 [(31.8%; 95% confidence interval (CI): 29–34%] and *4/*4 (18.2%; 95% CI: 16–21%). When grouped according to the expected phenotypical effects, the resulting genotypes revealed the significant prevalence of the subjects with slow (32.9%) and intermediate (48.9%) acetylation status compared with wild-type rapid (18.2%) acetylators ( P
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Arylamine N-Acetyltransferase 2 slow acetylator polymorphisms in unrelated Iranian individuals
European journal of clinical pharmacology, 2004Co-Authors: Valery V. Bakayev, F Mohammadi, Moslem Bahadori, Mariam Sheikholslami, Arash Javeri, Mohammad Reza Masjedi, Ali Akbar VelayatiAbstract:Objective To determine the frequency of mutations at the polymorphic gene coding for arylamine N-Acetyltransferase 2 (NAT2, EC 2.3.1.5) and NAT2 genotypes associated with slow acetylation in healthy Iranian individuals.
