Acetylator Phenotype Research Articles

1449. Therapeutic Drug Monitoring of Isoniazid and Rifampicin and Clinical Outcomes in Adults with Tuberculosis.

Abstract Background Directly Observed Treatment Short Course for Tuberculosis (TB) (DOTS) treatment currently produces a cure rate of 80%. Rifampicin (RMP) and isoniazid (INH) are the main bactericides; both show wide inter-individual pharmacokinetics and narrow therapeutic range. Therapeutic drug monitoring (TDM) of antiTB drugs is a strategy to improve the response to treatment. The aim of this work was to optimize and individualize antiTB treatment based on plasma concentrations of RMP and INH, NAT2 genotyping and the Bayesian estimation of PK parameters. Methods A prospective and analytical study including TB patients under DOTS scheme was performed. Venous blood samples were drawn 2 and 4 hours after last dose; INH and RMP were quantified by liquid chromatography coupled to tandem mass spectrometry. Anthropometric and clinical information was retrieved from medical records. Acetylator phenotype was determined based on NAT2 genotyping by real-time PCR. Bayesian estimation of the PK parameters was performed using NONMEM and dosing scheme was proposed to achieve therapeutic concentrations of RIF and INH. Results A total 62 patients were included from 18 to 80 years and 35 to 117 kg of total body weight. The most frequent was pulmonary infection (40%), 25% of patients had type 2 diabetes mellitus and 58.5% were slow acetylators for the NAT2 gene. Lower INH and RMP plasma concentrations were related to adverse clinical outcome, compared to those patients classified with early clinical success [1.9 vs 3.7 mg/L and 16.9 vs 10.0 mg/L (p< 0.05)]. Results indicate the need to adjust anti-TB drugs dose to more than 50% of the patients who show plasma concentrations outside the range for both drugs. Bayesian dosing performed was validated after individualization by quantification and interpretation of INH and RMP plasma concentrations followed by a narrow medical follow up. Conclusion Even with standard anti-TB treatment, great proportion of patients show subtherapeutic concentrations of RMP and INH which is associated with overall therapeutic failure. TDM is a useful tool to individualize antimicrobials dose and improve clinical outcomes at early stages of active TB. Disclosures All Authors: No reported disclosures.

Association between cigarette smoking and ovarian reserve among women seeking fertility care.

This study examined the association of smoking with ovarian reserve in a cross-sectional study of 207 women enrolled in the Louisville Tobacco Smoke Exposure, Genetic Susceptibility, and Infertility (LOUSSI) Study and assessed effect modification by NAT2 acetylator phenotype. Information on current smoking status was collected using a structured questionnaire and confirmed by cotinine assay. Serum anti-Müllerian hormone (AMH) levels were used to assess ovarian reserve. Diminished ovarian reserve (DOR) was defined as AMH <1ng/mL. Single nucleotide polymorphisms in the NAT2 gene, which metabolizes toxins found in cigarette smoke, were analyzed to determine NAT2 acetylator status. Linear and logistic regression were used to determine the effects of smoking on ovarian reserve and evaluate effect modification by NAT2. Regression analyses were stratified by polycystic ovary syndrome (PCOS) status and adjusted for age. Current smoking status, either passive or active as measured by urinary cotinine assay, was not significantly associated with DOR. For dose-response assessed using self-report, the odds of DOR increased significantly for every additional cigarette currently smoked (Odds ratio, OR:1.08; 95% confidence interval, 95%CI:1.01-1.15); additionally, every 1 pack-year increase in lifetime exposure was associated with an increased odds of DOR among women without PCOS (OR: 1.08 95%CI: 0.99-1.18). These trends appear to be driven by the heavy or long-term smokers. Effect modification by NAT2 genotype was not established. A history of heavy smoking may indicate increased risk of diminished ovarian reserve.

Accumulation and distribution of persistent organic pollutants in surface sediment of the estuarine region and correlation between genetic and environmental factors: A case study

In this study, the accumulation and distribution of nine organochlorine pesticides (OCPs) and seven polychlorinated biphenyls (PCBs) in the An Hoa Estuary, Quang Nam Province, Central Vietnam, and the correlation between genetic and environmental factors have been analyzed and assessed. This study analyzed sediment samples from 15 positions in the An Hoa Estuary during the dry season. The OCP concentrations varied between ND (not detected) and 1.82 μ g/kg (S1), mainly consisting of DDE. The total concentration of PCBs ranged between 1.52–19.5 μ g/kg (highest at S13), with PCB-138 and PCB-153 as the congeners most frequently detected in the analyzed samples. The results show that the ecological risk of OCPs and PCBs in the An Hoa Estuary ranges from low to moderate levels. In order to clarify the significance of genetic factors that can be influenced and affected by environmental factors over a certain period, this study also determined the N-acetyltransferase (NAT) enzyme activity in the population residing in the An Hoa Estuary for a period of 30–50 years to show clearly the relationship between weak environmental and genetic factors in determining the risks for environmental health. Based on the results, out of a total of 72 volunteer participants, the phenotype of the N-acetyltransferase system was determined and divided into two groups: rapid (30.6%) and slow (69.4%). Among them, the slow acetylator phenotype is prevalent in two locations, S11 and S13, with 88% and 91.7% of volunteers, respectively. The rapid acetylator phenotype was detected in 17 of 23 participants at location S7, accounting for more than 77% of the total individuals with the rapid acetylator phenotype in this experiment. • The accumulation of nine OCPs and seven PCBs in sediment was determined and assessed. • The highest OCPs (1.82 μ g/kg) and PCBs (19.5 μ g/kg) were detected at sampling sites S1 and S13, respectively. • The activity of xenobiotics biotransformation enzymatic system N-acetyltransferase was determined. • The relationship between weak environmental factors and genetic factors was examined. • The N-acetyltransferase phenotype of citizens was divided into rapid (30.6%) and slow (69.4%).

Very important pharmacogenes polymorphism landscape and potential clinical relevance in the Chinese Mongolian

PurposeOur study genotyped pharmacogenes in 200 individuals from Inner Mongolia Autonomous Region, China. Aim to find distinct pharmacogenomic variations among the Mongolian population and to investigate the potential clinically operable gene-drug connection and genotype-phenotype correlation of differential variation in the Mongolian population. MethodsWe sampled 61 variations of 28 genes in PharmGKB and genotyped them using Agena MassARRAY Assay. We also obtained the allele frequency and genotype distribution data of 26 populations from the 1000 Genomes Project (1000G), and then conducted comparison and statistical analysis. ResultsAfter Bonferroni correction, there were significant genotype frequency distribution differences between the Mongolian and 26 populations: PTGS2 (rs20417), NAT2 (rs1801280, rs1799929, and rs1208), ALOX5(rs2115819), and CYP2D6 (rs1065852). It was also found that the KHV showed the smallest differences from the Mongolian and the GWD showed the largest differences. Furthermore, the differences in variants might be related to the risk of non-steroidal anti-inflammatory drug use, the slow acetylation phenotype, and other pharmacological effectiveness and toxicity in the Mongolian population. ConclusionOur study demonstrates different pharmacogenomic variants in the Mongolian and fills the gaps in pharmacogenomic information of the Mongolian. Our analysis of VIPs variants in the Mongolian population may contribute to the development of safer treatment regimens and the use of personalized treatment approaches.

Clinical Prediction of Acetylator Phenotype in Tuberculosis Patients on Medicare using Blood Group

ABSTRACT Individual acetylation phenotype detected by metabolic phenotyping tests using a number of surrogate drugs, such as isoniazid is time consuming. The aim of this work was to determine the clinical prediction of acetylator phenotype in tuberculosis patients on medicare using blood group. 150 Tuberculosis patients (102 males and 48 females) on medicare were examined using urinalysis technique for acetylator status and tile method for blood group analysis. The result of the acetylator phenotypes revealed that 46.7% were fast acetylators while 53.3% were slow acetylators. The highest frequency of fast acetylators were subjects with blood groups O+ve and A+ve. Similarly, the highest frequency of slow acetylators were observed in blood groups B+ve and O+ve. Blood groups AB-ve and B-ve formed the lowest frequency of fast acetylators while A-ve and AB-ve formed the lowest percentage of slow acetylators respectively. Analysis of the blood groups and the acetylator phenotype using Pearson’s correlation showed a significant (p &lt; 0.01) relationship with a coefficient of 0.852; between the blood groups of M.Tb patients and the fast and slow acetylators (p &lt; 0.05, with a coefficient of 0.76) respectively. We imply that for standard TB treatment, more treatment time be considered for subjects with blood groups that are predominantly fast acetylators (e.g., O+ve ) and close monitoring through the treatment period for predominantly slow acetylators (e.g B+ve). Further study on the serum concentration of each blood group for the drugs and molecular analysis of the blood phenotypes is advocated. reby recommended.

Pharmacogenetic testing for NAT2 genotypes in a Tanzanian population across the lifespan to guide future personalized isoniazid dosing

Despite updated recommendations for weight-based isoniazid dosing in children with drug-susceptible tuberculosis (TB) and higher dose isoniazid in regimens for adults with drug-resistant TB, individual pharmacokinetic variability can lead to sub-target isoniazid exposure. Host pharmacogenetics and isoniazid exposure remain understudied, especially in the East African population. We therefore employed a real-time polymerase chain reaction (qPCR) assay system to test genomic DNA extracted from saliva samples targeting the NAT2 gene responsible for isoniazid metabolism to describe the frequency of human single nucleotide polymorphisms in NAT2 within populations of children and adults in Tanzania, ascribe those polymorphisms to acetylator phenotype, and correlate to serum isoniazid exposures. In adults treated with higher dose isoniazid, genotypes with a predicted allelic phenotype of slow or intermediate acetylation were able to achieve a 0.41 μg/mL higher Cmax (p = 0.018) and a 2.9h*μg/mL higher AUC0–12 (p = 0.003) per mg/kg increase in isoniazid dosage versus adults with rapid acetylation phenotype. A similar relationship was not found in the younger age population as predicted by timing of NAT2 maturation. This saliva based qPCR assay was fieldable to guide personalized isoniazid dosing in adults but not young children that may not have full NAT2 maturation and activity.

A Method to Determine Xenobiotic Acetylation Rate by Taq SNP rs1495741.

Drug acetylation plays an important role in the medical practice. Modern methods of acetylation phenotype prediction are based on genotyping of polymorphisms in the second exon of the gene NAT2. Some disadvantages of these methods limit their application in the clinical practice. We developed a method of human genotyping based on identification of NAT2 gene polymorphism rs1495741 by real-time PCR. This method of genotype determination has a number of advantages: high sensitivity, simplicity, possibility of automated interpretation of the results, and feasibility in clinical laboratories.

Expression of arylamine N-acetyltransferase 2 activity in immortalized human bronchial epithelial cells

Lung cancer is the leading cause of cancer deaths in the United States with high incidence in tobacco smokers. Arylamine N-acetyltransferase 2 (NAT2) is a xenobiotic enzyme that catalyzes both N- and O-acetylation of carcinogens present in tobacco smoke and contributes towards the genotoxicity of these carcinogens. NAT2 allelic variants result in slow, intermediate, and rapid acetylation phenotypes. A recent meta-analysis reported NAT2 non-rapid (slow and intermediate) phenotypes had a significantly increased risk of lung cancer. NAT2 activity in humans is thought to be restricted to liver and gastrointestinal tract, and no studies to our knowledge have reported the expression of NAT2 activity in immortalized human lung epithelial cells. Given the importance of NAT2 in cancer and inhalation of various carcinogens directly into the lungs, we investigated NAT2 activity in human lung epithelial cells. Both NAT1 and NAT2 protein were detected by “in-cell” Western. Arylamine N-acetyltransferase activity was determined with selective substrates for NAT1 (p-aminobenzoic acid; PABA) and NAT2 (sulfamethazine; SMZ) in the presence and absence of a selective NAT1 inhibitor. PABA N-acetylation (NAT1 activity) in cell protein lysates was abolished in the presence of 25 μM of NAT1 inhibitor whereas SMZ N-acetylation (NAT2) was unaffected. Incubation with the NAT1 inhibitor partially reduced the N-acetylation of β-naphthylamine and the O-acetylation of N-hydroxy-4-aminobiphenyl consistent with catalysis by both NAT1 and NAT2. Immortalized human lung epithelial cells exhibited dose-dependent N-acetylation of 4-ABP with an apparent KM of 24.4 ± 5.1 μM. These data establish that NAT2 is expressed and functional in immortalized human lung epithelial cells and will help us further our understanding of NAT2 in lung cancer.

From dietary adaptation in the past to drug metabolism of today: An example of NAT genes in the Croatian Roma

AbstractObjectivesThe evolutionary mechanisms that shape the genetic structure of a population left their mark on genes that metabolize drugs. The Roma are an example of a population in which the migrations, isolation, and multiple founder effects have affected its genetic structure. In this study, we investigated NAT1 and NAT2 genes, members of the xenobiotic‐metabolizing NAT gene family in three Roma groups from Croatia to explore the specificities of the Roma population in relation to other populations.Materials and MethodsSeven SNPs in the NAT1 gene and seven in the NAT2 gene were genotyped in 439 Roma from Croatia, members of three socio‐culturally different and geographically distant groups (two groups of Vlax/Bayash Roma and one Balkan Roma group). Intra‐ and inter‐population variation was assessed in the Roma and 2504 individuals from the 1000 Genomes project database.ResultsThe distribution of haplotypes differed significantly between the Roma groups for NAT2, but not for NAT1. Translation of NAT2 diplotypes into acetylation phenotypes showed significant differences between populations. The Roma from Balkan had the highest frequency of slow acetylators among the studied populations. In the overall worldwide sample, population differentiation was higher for NAT2 than for NAT1 haplotypes consistent with pairwise genetic distances that were smaller for NAT1 than for NAT2. The Ewens–Watterson test results suggest that NAT1 is subjected to directional selection, while NAT2 is evolving neutrally.ConclusionThe distribution of variations within NAT genes in the Croatian Roma population is similar to that in the surrounding European populations. The significantly different distribution of NAT2 gene haplotypes and consequent phenotypes between the three investigated Roma groups is probably the result of genetic drift due to different demographic history and socio‐cultural isolation. The highest frequency of slow acetylators in Balkan Roma compared to the world populations makes them more prone to develop a NAT gene‐related adverse drug reaction than other populations.

Development of population pharmacokinetics model of isoniazid in Indonesian patients with tuberculosis

ObjectivesNo population pharmacokinetics (PK) model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH on the basis of therapeutic drug monitoring (TDM) implementation in Indonesian patients with TB. Materials and methodsINH concentrations, N-acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model. ResultsA total of 107 patients with TB (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping. ConclusionsWe established the population PK model for INH in Indonesian patients with TB using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian patients with TB.

Correlation between N-Acetyltransferase 2 (NAT2) Polymorphism Genotype with Plasma Isoniazid (INH) Concentration in MDR TB Patients Receiving Short Regimen in West Sumatera

Background: Isoniazid (INH) is one of the most potent TB drug. High dose INH is used in short regimen MDR TB drugs. The genetic polymorphism of NAT2 affects the acetylation status. Awareness of the patients’ acetylator status is important to determine the risk of toxicity, treatment failure and drug resistance. The aim of this study was to demonstrate NAT2 genotype association with INH plasma concentration after 2 hours of oral INH therapy. Methods: This was a cross sectional study of MDR TB patients who received short term combination therapy at RSUP Dr. M.Djamil Padang, Achmad Muchtar Hospital Bukittinggiand West Sumatra Pulmonary Hospital from September 2019 to February 2020. Patients were examined for NAT2 genotype and plasma INH concentration. The results of the plasma INH concentrations obtained were evaluated based on the NAT2 acetylator phenotype group.Results: The majority of the subjects weremen (62.5%), aged 40-64 years (50%), had the most common comorbid of diabetes mellitus (31.25%), were normoweight (75%) and had negative HIV status (93.8%). A total of 7 alleles consisting of 7 SNPs and 7 variations of the NAT2 genotype were found in MDR TB patients who received short-term therapy. The NAT2*12A alleles (56.25%) was the most common allele and was a fast acetylator. Based on the bimodal distribution, the median concentration of INH in the fast and slow acetylator were 1.25 µg/ml and 5.24 µg/ml, respectively. The median values of INH concentration based on the trimodal distribution for fast, intermediate, and slow acetylators were 1.25 µg/ml, 2.17 µg/ml and 5.24 µg/ml. Conclusion: There were no correlations between the type of NAT2 acetylator phenotype and plasma INH concentrations.

Determination of the Isoniazid N-Acetylation Phenotype in a Sample Indian Population

An isoniazid N-acetylation phenotyping study was carried out in 200 human volunteers. A single urine sample taken 5 h post-isoniazid oral dose of 300 mg was analyzed and urinary concentrations of isoniazid and its metabolite acetylisoniazid were determined by high-performance liquid chromatography. Acetylator phenotype was determined from the metabolic ratio of N-acetylisoniazid to isoniazid concentration in the urine sample. The cut-off value, antimode, to distinguish between slow and fast acetylators was determined by probit analysis. Of the total 194 subjects phenotyped, 70.1 % were slow acetylators, 27.6 % were intermediate acetylators and 2.7 % were fast acetylators.

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs.

BACKGROUND Distinct N-acetyltransferase 2 (NAT2) slow acetylators genotypes have been associated with a higher risk to develop anti-tuberculosis drug-induced hepatotoxicity (DIH). However, studies have not pointed the relevance of different acetylation phenotypes presented by homozygotes and compound heterozygotes slow acetylators on a clinical basis.OBJECTIVES This study aimed to investigate the association between NAT2 genotypes and the risk of developing DIH in Brazilian patients undergoing tuberculosis treatment, focusing on the discrimination of homozygotes and compound heterozygotes slow acetylators.METHODS/FINDINGS The frequency of NAT2 genotypes was analysed by DNA sequencing in 162 patients undergoing tuberculosis therapy. The mutation analyses revealed 15 variants, plus two new NAT2 mutations, that computational simulations predicted to cause structural perturbations in the protein. The multivariate statistical analysis revealed that carriers of NAT2*5/*5 slow acetylator genotype presented a higher risk of developing anti-tuberculosis DIH, on a clinical basis, when compared to the compound heterozygotes presenting NAT2*5 and any other slow acetylator haplotype [aOR 4.97, 95% confidence interval (CI) 1.47-16.82, p = 0.01].CONCLUSION These findings suggest that patients with TB diagnosis who present the NAT2*5B/*5B genotype should be properly identified and more carefully monitored until treatment outcome in order to prevent the occurrence of anti-tuberculosis DIH.

Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.

Ontogeny of Pediatric Pharmacogenetics: Celebrating the Past and Vision for the Future.

Association of N-acetyltransferases 1 and 2 Polymorphisms with Susceptibility to Head and Neck Cancers-A Meta-Analysis, Meta-Regression, and Trial Sequential Analysis.

Background and objective:N-acetyltransferases 1 and 2 (NAT1 and NAT2) genes have polymorphisms in accordance with slow and rapid acetylator phenotypes with a role in the development of head and neck cancers (HNCs). Herein, we aimed to evaluate the association of NAT1 and NAT2 polymorphisms with susceptibility to HNCs in an updated meta-analysis. Materials and methods: A search was comprehensively performed in four databases (Web of Science, Scopus, PubMed/Medline, and Cochrane Library until 8 July 2021). The effect sizes, odds ratio (OR) along with 95% confidence interval (CI) were computed. Trial sequential analysis (TSA), publication bias and sensitivity analysis were conducted. Results: Twenty-eight articles including eight studies reporting NAT1 polymorphism and twenty-five studies reporting NAT2 polymorphism were involved in the meta-analysis. The results showed that individuals with slow acetylators of NAT2 polymorphism are at higher risk for HNC OR: 1.22 (95% CI: 1.02, 1.46; p = 0.03). On subgroup analysis, ethnicity, control source, and genotyping methods were found to be significant factors in the association of NAT2 polymorphism with the HNC risk. TSA identified that the amount of information was not large enough and that more studies are needed to establish associations. Conclusions: Slow acetylators in NAT2 polymorphism were related to a high risk of HNC. However, there was no relationship between NAT1 polymorphism and the risk of HNC.

&lt;i&gt;NAT2&lt;/i&gt; and &lt;i&gt;CYP1B1&lt;/i&gt; genetic polymorphisms in patients with genital endometriosis depending on tolerability of melatonin

BACKGROUND: Genital endometriosis is one of the most pressing problems of modern gynecology. Melatonin is a promising drug with a potentially curative effect on endometriosis.&#x0D; AIM: The aim of this study was to conduct a comparative analysis of the genetic polymorphism of some genes encoding enzymes involved in melatonin metabolism.&#x0D; MATERIALS AND METHODS: The genetic polymorphism in the NAT2 and CYP1B1 genes encoding enzymes involved in melatonin metabolism in patients with different tolerance to this drug was analyzed by PCR-RFLP analysis.&#x0D; RESULTS: In patients with genital endometriosis, the presence of a wild-type allele (N) of the NAT2 gene was associated with poor tolerance of melatonin. The NAT2 (N / N) rapid acetylator phenotype combined with the low catalytic activity of CYP1B1 (C / C) occurred more frequently in endometriosis patients having poor melatonin tolerability compared to the group of patients who tolerated the therapy well.&#x0D; CONCLUSIONS: For patients with genital endometriosis with the wild-type (N) allele of the NAT2 gene, melatonin administration is inappropriate due to numerous side effects during the drug use.

Особливості клітинної ланки імунної відповіді школярів, хворих на бронхіальну астму пізнього початку, залежно від ацетиляторного поліморфізму

Актуальність. Бронхіальна астма — одне з найбільш поширених захворювань у світі, кількість хворих на яке постійно збільшується, особливо серед дітей. Вважають, що неефективність контролюючої терапії астми, що відмічається практично в половини хворих, зумовлена, зокрема, наявністю різних астма-фенотипів. Мета дослідження: для оптимізації контролю астми пізнього початку оцінити окремі показники клітинної ланки імунної системи в школярів з урахуванням ацетиляторних фенотипів. Матеріал та методи. У пульмонологічному відділенні Обласної дитячої клінічної лікарні м. Чернівців обстежені 72 школярі, хворі на астму пізнього початку (захворювання вперше проявлялось у віці понад 6 років). Залежно від перебігу захворювання дітей розподіляли на дві клінічні групи. До першої групи увійшли 34 пацієнти, в яких визначали повільний тип ацетилювання (середній відсоток ацетильованого сульфадимезину в сечі становив менше 75,0 %). Другу клінічну групу сформували 38 школярів, у яких відмічався швидкий тип ацетилювання (середній відсоток ацетильованого сульфадимезину в сечі становив більше 75,0 %). Усім дітям методом імунофлуоресценції з використанням наборів моноклональних антитіл визначали вміст Т-лімфоцитів, Т-хелперів, Т-кілерів/Т-супресорів та В-лімфоцитів крові. Результати. Ацетилювання повільного типу в дітей, хворих на астму пізнього початку, підвищувало ризик зниження рівня CD3 у периферичній крові практично втричі. У кожної другої дитини (54,1 ± 10,1 %) за наявності повільного характеру ацетилювання при фенотипі астми пізнього початку реєструвався знижений вміст CD8 (менше 18,0 Г/л), а в групі порівняння — тільки в 21,0 ± 9,3 % пацієнтів (Р &lt; 0,05). Висновки. У більшості пацієнтів із повільним ацетиляторним фенотипом перебіг бронхіальної астми пізнього початку асоціюється зі зниженням вмісту CD3, CD4, CD8 у периферичній крові та В-лімфоцитів, що опосередковано свідчить про вираженість хронічного запального алергічного процесу в даної когорти осіб та виснаженість організму.

Modifying Effect of Smoking on GSTM1 and NAT2 in Relation to the Risk of Bladder Cancer in Mongolian Population: A Case-Control Study.

Objectives:Tobacco smoking is the predominant risk factor for bladder cancer as it contains cancer-causing chemicals. However, genetic factors may play important role in response towards chemical carcinogens. In this study we aim to investigate genetic polymorphisms of glutathione S-transferase M1 (GSTM1) and N-acetyltransferase 2 (NAT2) as determinants of bladder cancer risk, independently and in combination with tobacco use in the Mongolian population. Materials and Methods:The current study was a hospital-based case-control study including 60 histologically confirmed bladder cancer patients and 60 cancer-free controls. PCR-RFLP assay was used to determine the presence of GSTM1 and NAT2 polymorphisms in bladder cancer patients and controls. GSTM1 and NAT2 were tested using binary logistical regression analysis with adjustment or stratification according to the smoking. Results:There were 46 men and 14 women diagnosed with bladder cancer, with mean age was 58±4. The controls included 37 men and 23 women with a mean age of 57±3. The frequency of GSTM1 null genotype was higher in controls (71.67%) than in bladder cancer patients (58.33%) without statistical significance (OR=0.5534; 95% CI=0.2586-1.1843), (p=0.128). The NAT2 low acetylator phenotype was more common in patients with bladder cancer (15%) than in controls (5%). Furthermore, individuals with NAT2 low acetylator phenotype had a nearly 3.35-fold increased risk to develop bladder cancer (OR=3.35; 95% CI=0.8604-13.0657), (p=0.081) while the risk was even higher when combined with null GSTM1 genotype (OR=4; 95% CI=0.4459-37.5308), (p=0.213) but there was no statistical significance. Prevalence of smoking in bladder cancer patients was higher than controls and increased significantly the risk of bladder cancer (OR=8.31; 95% CI=3.66-18.88). Smokers with GSTM1 null genotype were at 5-fold higher risk of bladder cancer (OR=5.0; 95% CI=1.55-16.16), (p=0.007) while NAT2 low acetylator phenotype increased bladder cancer risk by 20-fold (OR=20.5; 95% CI=2.33-80.86), (p=0.006). Conclusion:The current study shows that tobacco smokers with the NAT2 low acetylator phenotype and GSTM1 null genotype have the highest risk of bladder cancer in the Mongolian population.

Isoniazid Population Pharmacokinetics and Dose Recommendation for Korean Patients With Tuberculosis Based on Target Attainment Analysis.

The wide variability of isoniazid (INH) pharmacokinetics is mainly attributed to the trimodal N-acetyltransferase 2 (NAT2) acetylator phenotype, that is, rapid, intermediate, and slow. Consequently, a uniform INH dose in current clinical practice may lead to treatment failure and emergence of drug resistance. There is a lack of studies on specific doses of INH for different NAT2 acetylator phenotypes among tuberculosis (TB) patients. Therefore, we aimed to provide insight into the optimal dosing of INH for each NAT2 acetylator phenotype with respect to the probability of achieving a pharmacokinetic (PK)/pharmacodynamic target. PK, the NAT2 genotype, and clinical data were collected in a multicenter prospective cohort study conducted at 13 clinical centers in Korea. Population PK modeling and simulation were carried out. Data from 454 TB patients were divided into a training data set and a test data set at a ratio of 4 to 1. The PK of the training data were best described by a 2-compartment model with allometric scaling for body size effect. Importantly, NAT2 acetylator phenotypes significantly affected the apparent clearance. Our model, which provided better predictive performance compared with previously published models, was evaluated by external validation using the test set. The simulation for assessing target efficacy and toxicity indicated that the best INH dosing regimens for Korean tuberculosis patients were once-daily doses of 400, 300, and 200 mg for rapid, intermediate, and slow acetylators, respectively. In conclusion, our study provides a step forward in precision dosing for antituberculosis management.

Acetylator Status Among Newly Diagnosed and Recurrent Tuberculosis Patients from Kupang, Eastern Part of Indonesia.

PurposeN-acetyltransferase-2 enzyme in the liver, encoded by NAT2 gene, plays a central role in metabolizing tuberculosis (TB) drug isoniazid (INH). Low compliance of patients toward six-month TB therapy and internal host factors, ie comorbid diseases, immune status, and genetic profiles, are factors leading to treatment failure and recurrence of pulmonary TB infection. This study aimed to explore the NAT2 acetylator status among newly diagnosed and recurrent pulmonary TB patients in eastern part of Indonesia.Patients and MethodsArchived DNA of TB patients (n=124) and healthy controls (n=124) were sequenced, and NAT2 acetylator status was determined, then categorized as fast, intermediate, or slow acetylators. Pulmonary TB patients who had no previous TB treatment history were designated as newly diagnosed pulmonary TB, whereas patients with a history of TB treatment were designated as recurrent pulmonary TB. The demographic, clinical, and microbiological data between pulmonary TB groups were compared, and acetylator status was described among groups.ResultsMale was more significantly prevalent in the recurrent pulmonary TB group (p=0.025), and anemia was more prevalent in new pulmonary TB (p=0.003). The acetylator status in pulmonary TB patients compared to healthy controls were rapid (33.9% vs 48.1%), intermediate (57.8% vs 33.0%), and slow acetylators (8.3% vs 18.9%), respectively. Interestingly, the rapid and intermediate acetylator were significantly more prevalent in pulmonary TB patients than in healthy controls (p=0.023, OR=2.58 (1.12–5.97). Furthermore, no differences were found in acetylator status between new and recurrent pulmonary (p=0.776).ConclusionRapid and intermediate acetylators status predominated the pulmonary TB patients in Kupang, eastern part of Indonesia, postulating different genetic makeup in this area. As the pulmonary TB patients in Kupang exhibit more rapid acetylator phenotype, the acetylator status might be relevant to be checked before TB therapy for adjusting treatment dose to prevent drug resistances.