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Thomas L, Chaithra, Batra Y, Mathur M, Kulavalli S, SV CS, Dutt N, Bhardwaj P, Varma M, Saravu K, Banerjee M, Rao M. Pharmacogenomic heterogeneity of N-acetyltransferase 2: a comprehensive analysis of real world data in Indian tuberculosis patients and from literature and database review. Ann Med 2025; 57:2478316. [PMID: 40138446 PMCID: PMC11948353 DOI: 10.1080/07853890.2025.2478316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 01/06/2025] [Accepted: 01/31/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Isoniazid is primarily metabolized by the arylamine N-acetyltransferase 2 (NAT2) enzyme. Single nucleotide polymorphisms (SNPs) in the NAT2 gene could classify an individual into three distinct phenotypes: rapid, intermediate and slow acetylators. NAT2 SNPs and the slow acetylator phenotype have been implicated as risk factors for the development of antitubercular drug-induced liver injury (AT-DILI) in several tuberculosis (TB) populations. PATIENTS AND METHODS We conducted a prospective observational study to characterize and compare the NAT2 SNPs, genotypes and phenotypes among patients with TB and AT-DILI from the Southern and Western regions of India. The NAT2 pharmacogenomic profile of patients from these regions was compared with the reports from several geographically diverse TB populations and participants of different genetic ancestries extracted from literature reviews and the 'All of Us' Research Program database, respectively. RESULTS The TB patients of Southern and Western regions of India and several other geographically closer regions exhibited near similar NAT2 MAF characteristics. However significant heterogeneity in NAT2 SNPs was observed within and between countries among AT-DILI populations and the participants of different genetic ancestry from the 'All of Us' Research Program database. The MAF of the NAT2 SNPs rs1041983, rs1801280, rs1799929, rs1799930 and rs1208 of the TB patients from Southern and Western Indian Sites were in near range to that of the South Asian genetic ancestry of 'All of Us' Research Program database. About one-third of the total TB patients from the Southern and Western regions of India were NAT2 slow acetylators, among whom a relatively higher proportion experienced AT-DILI. CONCLUSION Further studies exploring the risk of NAT2 SNPs in different AT-DILI patients with larger sample sizes and a population-specific approach are required to establish a policy for NAT2 genotyping as a pre-emptive biomarker for AT-DILI monitoring for personalized isoniazid therapy in clinics.
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Affiliation(s)
- Levin Thomas
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Chaithra
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Yashi Batra
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
- Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, USA
| | - Mitali Mathur
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Shrivathsa Kulavalli
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
| | | | - Naveen Dutt
- Department of Pulmonary Medicine, All India Institute of Medical Sciences, Jodhpur, India
| | - Pankaj Bhardwaj
- Department of Community Medicine and Family Medicine, All India Institute of Medical Sciences, Jodhpur, India
| | - Muralidhar Varma
- Department of Infectious Diseases, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Kavitha Saravu
- Department of Infectious Diseases, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India
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Cheli S, Torre A, Schiuma M, Montrasio C, Civati A, Galimberti M, Battini V, Mariani I, Mosini G, Carnovale C, Radice S, Clementi E, Gori A, Antinori S. NAT2 Slow Acetylator Phenotype as a Significant Risk Factor for Hepatotoxicity Caused by Antituberculosis Drugs: Results From a Multiethnic Nested Case-Control Study. Clin Infect Dis 2024:ciae583. [PMID: 39727196 DOI: 10.1093/cid/ciae583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Under standard therapies, the incidence of drug-induced liver injury (DILI) in patients with tuberculosis ranges from 2% to 28%. Numerous studies have identified the risk factors for antituberculosis DILI; however, none have been conducted in a multiethnic real-world setting. The primary outcome of the current study was to identify the risk factors that could be used as the best predictors of DILI in a multiethnic cohort. METHODS A nested case-control study was conducted in patients at the tuberculosis clinic of Luigi Sacco Hospital in Milan. RESULTS The study included 102 patients (mean age [SD], 45.6 [15.6] years). For each patient with hepatotoxicity, 2 controls were matched for sex, age, body mass index, tuberculosis/tuberculosis infection diagnosis, and index date. We found that N-acetyltransferase 2 gene (NAT2) slow acetylator status was the best independent predictor of DILI (odds ratio, 5.97 [95% confidence interval, 1.38-25.76]; P = .02]. CONCLUSIONS NAT2 genotype-guided dosing may help optimize antituberculosis drug treatment and prevent treatment failure. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov NCT06539455.
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Affiliation(s)
- Stefania Cheli
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
| | - Alessandro Torre
- III Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
| | - Marco Schiuma
- II Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
| | - Cristina Montrasio
- Center of Functional Genomics and Rare Diseases, Buzzi Children's Hospital, Milan, Italy
| | - Aurora Civati
- Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Miriam Galimberti
- Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Vera Battini
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
| | - Ilaria Mariani
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
| | - Giulia Mosini
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
| | - Carla Carnovale
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
| | - Sonia Radice
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
| | - Emilio Clementi
- ICPS, Pharmacovigilance & Clinical Research, Department of Biomedical and Clinical Sciences, ASST Fatebenefratelli Sacco, University Hospital Luigi Sacco, Università Degli Studi di Milano, Milan, Italy
- III Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
- II Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
- Center of Functional Genomics and Rare Diseases, Buzzi Children's Hospital, Milan, Italy
- Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milan, Italy
- Scientific Institute, IRCCS E. Medea, Bosisio Parini, LC, Italy
| | - Andrea Gori
- II Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
- Center of Functional Genomics and Rare Diseases, Buzzi Children's Hospital, Milan, Italy
- Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Spinello Antinori
- III Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
- II Infectious Disease Unit, ASST Fatebenefratelli Sacco, Luigi Sacco Hospital, Milan, Italy
- Center of Functional Genomics and Rare Diseases, Buzzi Children's Hospital, Milan, Italy
- Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milan, Italy
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Mahajan R, Tyagi AK. Pharmacogenomic insights into tuberculosis treatment shows the NAT2 genetic variants linked to hepatotoxicity risk: a systematic review and meta-analysis. BMC Genom Data 2024; 25:103. [PMID: 39639188 PMCID: PMC11622454 DOI: 10.1186/s12863-024-01286-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Tuberculosis (TB) patients undergoing anti-tuberculosis treatment often face serious adverse drug reactions, such as hepatotoxicity. Genetic variants of the N-acetyltransferase 2 (NAT2) gene have been linked to an increased risk of these toxic events. OBJECTIVE This study aims to provide a comprehensive evaluation of the evidence linking NAT2 genetic variants to anti-tuberculosis drug-related hepatotoxicity (ATDH). METHOD A comprehensive review and meta-analysis was performed by accessing databases such as PubMed, Scopus, and Web of Science. A total of 24 articles were incorporated into the dataset. Meta-analyses were conducted to gather estimates of the association between the slow acetlylators (SA) genotype and ATDH. The studies were stratified by ethnicity, regimen, genotyping methods, criteria for liver toxicity, and dosage. Also, meta-analysis for the specific SA type that was most likely responsible for the ATDH was also conducted. RESULTS The included studies showed individuals with a slow NAT2 acetylator had a significantly greater risk of experiencing hepatotoxicity ATDH (odds ratio [OR] 2.52 (95% CI: 1.95-3.27; p value < 0.001) compared to individuals with other types of acetylator (i.e., rapid and immediate). Among individuals with slow acetylator NAT2*5/7, NAT2*5/6, and NAT2*6/6 genotypes, there is a greater likelihood of association compared to other variations. CONCLUSION Our meta-analysis confirms a significant association between slow NAT2 acetylator and increased hepatotoxicity risk. The findings from the present underscore the potential of pharmacogenomic testing to improve TB treatment outcomes. By identifying patients with the slow acetylator NAT2 genotype, healthcare providers can predict an increased risk of anti-tuberculosis drug-induced hepatotoxicity. This allows for personalized treatment strategies, such as adjusting drug dosages or selecting alternative therapies, to minimize adverse effects and optimize efficacy.
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Affiliation(s)
- Rashmi Mahajan
- Dr. Bhimrao Ramji Ambedkar Government Medical College, Kannauj, India
| | - Anuj Kumar Tyagi
- Dr. Bhimrao Ramji Ambedkar Government Medical College, Kannauj, India.
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Perini JA, Basta PC, Cardoso JV, Elias ABR, Suarez-Kurtz G. Differential distribution of NAT2 polymorphisms and NAT2 acetylator phenotypes among indigenous populations of the Brazilian Amazon. Pharmacogenet Genomics 2024; 34:269-274. [PMID: 39259702 DOI: 10.1097/fpc.0000000000000544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2024]
Abstract
OBJECTIVES We report, for the first time, the distribution of four no-function NAT2 single nucleotide polymorphisms and inferred NAT2 acetylator phenotypes in three indigenous groups (Munduruku, Paiter-Suruí, and Yanomami), living in reservation areas in the Brazilian Amazon. METHODS Two hundred and seventy-six participants from three indigenous groups (92 for each group) were included and genotyped for four NAT2 polymorphisms (rs1801279, rs1801280, rs1799930, and rs1799931) by the TaqMan system. Minor Allele Frequency (MAF) was determined and NAT2 acetylator phenotypes were inferred. RESULTS NAT2 rs1801279G>A was absent in all cohorts; rs1799930G>A was absent in Yanomami and rare (MAF 0.016) in Munduruku and Paiter-Suruí; MAF of rs1801280T>C ranged five-fold (0.092-0.433), and MAF of rs1799931G>A varied between 0.179 and 0.283, among the three groups. The distribution of NAT2 phenotypes differed significantly across cohorts; the prevalence of the slow acetylator phenotype ranged from 16.3% in Yanomami to 33.3% in Munduruku to 48.9% in Paiter-Suruí. This three-fold range of variation is of major clinical relevance because the NAT2 slow phenotype is associated with higher risk of hepatotoxicity with antituberculosis chemotherapy and high incidence rates of tuberculosis and burden of latent infection among Munduruku, Paiter-Surui, and Yanomami peoples. According to the frequency of the NAT2 slow acetylator phenotype, the estimated number of individuals needed to be genotyped to prevent one additional event of hepatotoxicity range from 31 (Munduruku) to 39 (Paiter-Surui) and to 67 (Yanomami). CONCLUSION The rs1801279 polymorphism was not found in any of the cohorts, while the MAF of the other polymorphisms showed significant variation between the cohorts. The difference in the prevalence of the NAT2 slow acetylator phenotype, which is linked to isoniazid-induced hepatotoxicity, was observed in the different study cohorts.
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Affiliation(s)
- Jamila A Perini
- Departamento de Farmácia, Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil
| | - Paulo C Basta
- Departamento de Endemias Samuel Pessoa, Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz (ENSP/Fiocruz), Rio de Janeiro, Brazil
| | - Jessica V Cardoso
- Departamento de Farmácia, Laboratório de Pesquisa de Ciências Farmacêuticas (LAPESF), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil
| | - Anna Beatriz R Elias
- Departamento de Pesquisa, Divisão de Pesquisa Clínica e Desenvolvimento Tecnológico, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
| | - Guilherme Suarez-Kurtz
- Departamento de Pesquisa, Divisão de Pesquisa Clínica e Desenvolvimento Tecnológico, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil
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Sankar J, Chauhan A, Singh R, Mahajan D. Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement. Front Pharmacol 2024; 15:1441147. [PMID: 39364056 PMCID: PMC11447295 DOI: 10.3389/fphar.2024.1441147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/30/2024] [Indexed: 10/05/2024] Open
Abstract
Despite the extraordinary anti-tubercular activity of isoniazid (INH), the drug-induced hepatotoxicity and peripheral neuropathy pose a significant challenge to its wider clinical use. The primary cause of INH-induced hepatotoxicity is in vivo metabolism involving biotransformation on its terminal -NH2 group owing to its high nucleophilic nature. The human N-acetyltransferase-2 enzyme (NAT-2) exploits the reactivity of INH's terminal -NH2 functional group and inactivates it by transferring the acetyl group, which subsequently converts to toxic metabolites. This -NH2 group also tends to react with vital endogenous molecules such as pyridoxine, leading to their deficiency, a major cause of peripheral neuropathy. The elevation of liver functional markers is observed in 10%-20% of subjects on INH treatment. INH-induced risk of fatal hepatitis is about 0.05%-1%. The incidence of peripheral neuropathy is 2%-6.5%. In this review, we discuss the genesis and historical development of INH, and different reported mechanisms of action of INH. This is followed by a brief review of various clinical trials in chronological order, highlighting treatment-associated adverse events and their occurrence rates, including details such as geographical location, number of subjects, dosing concentration, and regimen used in these clinical studies. Further, we elaborated on various known metabolic transformations highlighting the involvement of the terminal -NH2 group of INH and corresponding host enzymes, the structure of different metabolites/conjugates, and their association with hepatotoxicity or neuritis. Post this deliberation, we propose a hydrolysable chemical derivatives-based approach as a way forward to restrict this metabolism.
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Affiliation(s)
- Jishnu Sankar
- Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Anjali Chauhan
- Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
| | - Ramandeep Singh
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India
| | - Dinesh Mahajan
- Centre for Drug Discovery, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
- Centre for Tuberculosis Research, BRIC-Translational Health Science and Technology Institute, Faridabad, Haryana, India
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Thomas L, Raju AP, Chaithra S, Kulavalli S, Varma M, Sv CS, Baneerjee M, Saravu K, Mallayasamy S, Rao M. Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients. Expert Rev Clin Pharmacol 2024; 17:263-274. [PMID: 38287694 DOI: 10.1080/17512433.2024.2311314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 01/24/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). RESEARCH DESIGN AND METHODS A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. RESULTS NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators. CONCLUSION The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.
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Affiliation(s)
- Levin Thomas
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Arun Prasath Raju
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - S Chaithra
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shrivathsa Kulavalli
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Muralidhar Varma
- Department of Infectious Diseases, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | - Mithu Baneerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Kavitha Saravu
- Department of Infectious Diseases, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Surulivelrajan Mallayasamy
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Rivera JGB, Albério CAA, Vieira JLF. Influence of sex on the exposure to isoniazid in patients with pulmonary tuberculosis. Rev Inst Med Trop Sao Paulo 2023; 65:e56. [PMID: 37878973 PMCID: PMC10588987 DOI: 10.1590/s1678-9946202365056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/30/2023] [Indexed: 10/27/2023] Open
Abstract
Isoniazid is a key component of tuberculosis treatment. Adequate exposure is a determinant for therapeutic success; however, considerable inter- and intraindividual variations in drug plasma levels can lead to unfavorable outcomes. While some predictors of isoniazid levels are well-known, others, such as sex, yield controversial results, requiring further investigation to optimize exposure. This study investigates whether the sex of patients influences the dose administered and the concentrations of isoniazid in plasma. Levels of isoniazid were associated with the N-acetyltransferase 2 phenotypes. A total of 76 male and 58 female patients were included. Isoniazid was measured by high-performance liquid chromatography, and N-acetyltransferase 2 phenotypes were assessed using molecular techniques. The results show that the dose administered, expressed in mg/kg, was higher in females, but the plasma levels were similar between both sexes. Among patients, 46.2%, 38.8%, and 15% were slow, intermediate, and fast acetylators, respectively. As expected, isoniazid levels were associated with the acetylation phenotypes, with higher concentrations in the slow acetylators. Thus, sex-related difference in isoniazid levels is due to the body weight of patients, and the optimized dose regimen based on patient weight and acetylator phenotypes can improve the treatment outcomes.
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8
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Mohamed Noor NF, Salleh MZ, Mohd Zim MA, Bakar ZA, Fakhruzzaman Noorizhab MN, Zakaria NI, Lailanor MI, Teh LK. NAT2 polymorphism and clinical factors that increased antituberculosis drug-induced hepatotoxicity. Pharmacogenomics 2022; 23:531-541. [PMID: 35615896 DOI: 10.2217/pgs-2022-0022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Hepatotoxicity is a known adverse effect of antituberculosis drugs. The NAT2 gene polymorphism has been associated with an increased risk of antituberculosis drug-induced hepatotoxicity (ATDIH). Materials and methods: This study investigates the association of NAT2 polymorphism and clinical risk factors that may contribute to the development of ATDIH. The authors sequenced the NAT2 region of 33 tuberculosis patients who developed ATDIH and 100 tuberculosis patients who did not develop ATDIH during tuberculosis treatment. NAT2 haplotypes were inferred and NAT2 acetylator status was predicted from the combination of the inferred haplotypes. Multiple logistic regression was performed to identify possible factors that are associated with ATDIH. Results: The TT genotype of NAT2*13A and the AA genotype of NAT2*6B were found to be substantially linked with the risk of ATDIH, with odds ratios of 3.09 (95% CI: 1.37-6.95) and 3.07 (95% CI: 1.23-7.69), respectively. NAT2 slow acetylators are 3.39-times more likely to develop ATDIH. Factors that were associated with ATDIH include underlying diabetes mellitus (adjusted odds ratio [AOR] 2.96; 95% CI: 1.05-8.37), pre-treatment serum bilirubin (AOR 1.09; 95% CI: 1.02-1.16) and NAT2 slow acetylator (AOR 3.77; 95% CI: 1.51-9.44). Conclusion: Underlying diabetes mellitus, having a higher baseline bilirubin and being a slow acetylator are identified as the risk factors associated with ATDIH among patients in Malaysia.
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Affiliation(s)
- Nur Farhana Mohamed Noor
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia
| | - Mohd Zaki Salleh
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia.,Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia
| | - Mohd Arif Mohd Zim
- Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Selangor, 47000, Malaysia
| | - Zamzurina Abu Bakar
- Respiratory Medicine Institute, Ministry of Health Malaysia, Kuala Lumpur, 53000, Malaysia
| | - Mohd Nur Fakhruzzaman Noorizhab
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia.,Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia
| | - Noor Izyani Zakaria
- Medical Department, Selayang Hospital, Ministry of Health Malaysia, Batu Caves, Selangor, 68100, Malaysia
| | | | - Lay Kek Teh
- Integrative Pharmacogenomics Institute, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia.,Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, 42300, Malaysia
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9
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Chen Y, Guan S, Guan Y, Tang S, Zhou Y, Wang X, Bi H, Huang M. Novel Clinical Biomarkers for Drug-Induced Liver Injury. Drug Metab Dispos 2022; 50:671-684. [PMID: 34903588 DOI: 10.1124/dmd.121.000732] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022] Open
Abstract
Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight. Accordingly, in this minireview, we summarize recent advances in novel clinical biomarkers for DILI prediction, diagnosis, and prognosis and highlight the limitations or challenges involved in biomarker discovery or its clinical translation. Although huge work has been done, most reported biomarkers lack comprehensive information and more specific DILI biomarkers are still needed to complement the traditional biomarkers such as alanine aminotransferase (ALT) or aspartate transaminase (AST) in clinical decision-making. SIGNIFICANCE STATEMENT: This current review outlines an overview of novel clinical biomarkers for drug-induced liver injury (DILI) identified in clinical retrospective or prospective clinical analysis. Many of these biomarkers provide a mechanistic insight and are promising to complement the traditional DILI biomarkers. This work also highlights the limitations or challenges involved in biomarker discovery or its clinical translation.
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Affiliation(s)
- Youhao Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Shaoxing Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanping Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Siyuan Tang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanying Zhou
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Xueding Wang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Huichang Bi
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Min Huang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
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10
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El-Jaick KB, Ribeiro-Alves M, Soares MVG, Araujo GEFD, Pereira GRC, Rolla VC, Mesquita JFD, De Castro L. Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs. Mem Inst Oswaldo Cruz 2022; 117:e210328. [PMID: 35588539 PMCID: PMC9049236 DOI: 10.1590/0074-02760210328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 02/24/2022] [Indexed: 12/01/2022] Open
Abstract
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.
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Affiliation(s)
- Kenia Balbi El-Jaick
- Universidade Federal do Estado do Rio de Janeiro, Brazil; Universidade Federal do Estado do Rio de Janeiro, Brazil
| | | | | | | | | | | | - Joelma Freire De Mesquita
- Universidade Federal do Estado do Rio de Janeiro, Brazil; Universidade Federal do Estado do Rio de Janeiro, Brazil; Universidade Federal do Estado do Rio de Janeiro, Brazil
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11
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Headriawan A, Pramono AA, Sukadi A, Chairulfatah A, Maskoen AM, Nataprawira HM. NAT2 Gene rs1041983 is Associated with Anti-Tuberculosis Drug Induced Hepatotoxicity Among Pediatric Tuberculosis in Bandung, Indonesia. APPLICATION OF CLINICAL GENETICS 2021; 14:297-303. [PMID: 34113149 PMCID: PMC8184287 DOI: 10.2147/tacg.s303668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 04/23/2021] [Indexed: 12/30/2022]
Abstract
Background As pediatric tuberculosis (TB) globally is still reported challenging in diagnosis, to date, a lot of efforts have been established to eliminate the disease including proper treatment regimen using anti-TB drugs. However, antituberculosis drug-induced hepatotoxicity (ADIH) is known to interfere the success of the prescribed therapy. ADIH was found to be correlated with polymorphisms of NAT2 gene, that is responsible to transcript the NAT2 enzyme, a metabolizer of isoniazid (INH). The most common NAT2 gene polymorphisms in Asian population associated with ADIH are rs1041983, rs1799929, rs1799930 and rs1799931. The study aimed to investigate the 4 single nucleotide polymorphisms (SNPs) in pediatric TB that experienced ADIH. Methods We conducted a case-control study comparing 31 each of pediatric TB experience with and without ADIH. All pediatric TB was selected from 451 pediatric TB Registry of Respirology Division, Department of Child Health Faculty of Medicine Universitas Padjadjaran/Dr Hasan Sadikin Hospital during January 2016 to July 2018. Genomic DNA PCR and sequencing to identify polymorphisms of rs1041983, rs1799929, rs1799930 and rs1799931 were performed in both groups. Data analysis was performed using the Epi info Ver. 7 software. Results Thirty-one pediatric TB experiences with and without ADIH were enrolled in this study. SNP rs1041983 significantly affected the occurrence of ADIH (OR 2.39, CI 95% (1.15-4.96), p=0.019). The rs1799929, rs1799930 and rs1799931 did not significantly affect the occurrence of ADIH (p=0.133, p=0.150 and p=0.659, respectively). Conclusion Polymorphism SNP rs1041983 had association with the occurrence of ADIH.
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Affiliation(s)
| | | | | | | | - Ani Melani Maskoen
- Research Center of Medical Genetics.,Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital, Bandung, Indonesia
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12
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Becker MW, Schwambach KH, Lunardelli M, Blatt CR. Overview of drug induced liver injury in Brazil: What is the role of public health policy on the evidence? World J Gastrointest Pharmacol Ther 2021; 12:40-55. [PMID: 34046243 PMCID: PMC8134851 DOI: 10.4292/wjgpt.v12.i3.40] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/20/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adverse drug reactions are responsible for increased costs and morbidity in the health system. Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases. It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries. AIM To identify and to summarize Brazilian studies reporting the drug-induced liver injury. METHODS A systematic review of Brazilian studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported. RESULTS Twenty-two different criteria for hepatotoxicity were found. The great heterogeneity did not allow a meta-analysis. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury (DILI)'s epidemiology in Brazil. CONCLUSION The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care, two strategic health policies in Brazil.
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Affiliation(s)
- Matheus William Becker
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Karin Hepp Schwambach
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Michele Lunardelli
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
| | - Carine Raquel Blatt
- Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
- Pharmacoscience Department, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, RS, Brazil
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13
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Araujo-Mariz C, Militão de Albuquerque MDFP, Lopes EP, Ximenes RAA, Lacerda HR, Miranda-Filho DB, Lustosa-Martins BB, Pastor AFP, Acioli-Santos B. Hepatotoxicity during TB treatment in people with HIV/AIDS related to NAT2 polymorphisms in Pernambuco, Northeast Brazil. Ann Hepatol 2021; 19:153-160. [PMID: 31734174 DOI: 10.1016/j.aohep.2019.09.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 09/02/2019] [Accepted: 09/14/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVE Hepatotoxicity during tuberculosis (TB) treatment is frequent and may be related to the Arylamine N-Acetyltransferase (NAT2) acetylator profile, in which allele frequencies differ according to the population. The aim of this study was to investigate functional polymorphisms in NAT2 associated with the development of hepatotoxicity after initiating treatment for TB in people living with HIV/AIDS (PLWHA) in Pernambuco, Northeast Brazil. MATERIAL AND METHODS This was a prospective cohort study that investigated seven single nucleotide polymorphisms located in the NAT2 coding region in 173 PLWHA undergoing TB treatment. Hepatotoxicity was defined as elevated aminotransferase levels and identified as being three times higher than it was before initiating TB treatment, with associated symptoms of hepatitis. A further 80 healthy subjects, without HIV infection or TB were used as a control group. All individuals were genotyped by direct sequencing. RESULTS The NAT2*13A and NAT2*6B variant alleles were significantly associated with the development of hepatotoxicity during TB treatment in PLWHA (p<0.05). Individual comparisons between the wild type and each variant genotype revealed that PLWHA with signatures NAT2*13A/NAT2*13A (OR 4.4; CI95% 1.1-18.8; p 0.037) and NAT2*13A/NAT2*6B (OR 4.4; CI95% 1.5-12.7; p 0.005) significantly increased the risk of hepatotoxicity. CONCLUSION This study suggests that NAT2*13A and NAT2*6B variant alleles are risk factors for developing hepatotoxicity, and PLWHA with genotypes NAT2*13A/NAT2*13A and NAT2*13A/NAT2*6B should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis.
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Affiliation(s)
- Carolline Araujo-Mariz
- Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Recife, PE, Brazil.
| | | | - Edmundo P Lopes
- Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Ricardo A A Ximenes
- Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | - Heloísa R Lacerda
- Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Recife, PE, Brazil
| | | | | | - André Filipe P Pastor
- Instituto Federal de Educação, Ciência e Tecnologia do Sertão Pernambucano/IFSertão, Floresta, PE, Brazil
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14
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Galvão FES, Fonseca AAD, Pinto ACG, da Paixão TP, Albério CAA, Vieira JLF. No significant influence of diabetic mellitus on isoniazid plasma levels in patients under treatment for tuberculosis. Infect Dis (Lond) 2020; 52:577-580. [DOI: 10.1080/23744235.2020.1761561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
Affiliation(s)
| | | | - Ana Carla Godinho Pinto
- Pharmacy Faculty, Campus Universitario do Guama, Para Federal University, Belem, Para, Brazil
| | - Thiago Portal da Paixão
- Pharmacy Faculty, Campus Universitario do Guama, Para Federal University, Belem, Para, Brazil
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15
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Zhang D, Hao J, Hou R, Yu Y, Hu B, Wei L. The role of NAT2 polymorphism and methylation in anti-tuberculosis drug-induced liver injury in Mongolian tuberculosis patients. J Clin Pharm Ther 2020; 45:561-569. [PMID: 32364660 DOI: 10.1111/jcpt.13097] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 11/11/2019] [Accepted: 11/19/2019] [Indexed: 01/02/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE Anti-tuberculosis drug-induced liver injury (ATLI) is one of the most significant adverse reactions for this line of therapy. N-acetyltransferase 2 (NAT2) is an important metabolic enzyme involved in drug metabolism and detoxification. Genetic polymorphism and DNA methylation have been proven to be key factors that affect the expression of NAT2. Therefore, the objective of the study was to investigate the relationship between NAT2 gene polymorphism and DNA methylation in the promoter region with ATLI risk in Mongolian tuberculosis patients. METHODS Our study is a case-control design. Chi-square test, Mann-Whitney U non-parametric test and Pearson test were all used to analyse existing relationships. The association between NAT2 gene acetylation phenotype and the total methylation of the NAT2 promoter region was analysed by means of binary logistic regression analysis. The general situation of the patients was evaluated by questionnaire, and the NAT2 genotyping of the three major polymorphism loci of gene coding was carried out by a gene sequencing technique. The methylation status of the NAT2 gene promoter region was detected by bisulphite sequencing and mass spectrometry. RESULT AND DISCUSSION Our study found that the detection rate of ATLI in Mongolian tuberculosis patients was 27.6%. There were no significant differences in demographic characteristics and living habits amongst the two groups, while significant differences were observed in the polymorphism of the NAT2 genes 481 (rs1799929) and 590 (rs1799930) and the acetylation phenotype. Moreover, the composition and distribution of the NAT2*4/4 and NAT2*4/5 genotypes were found in the two groups. The risk of ATLI in the slow acetylation type was 3.56 times higher than that of the fast acetylation type. Compared with the control group, the CpG5, CpG10, CpG11.12 and total methylation of the NAT2 promoter region in the ATLI group showed a hypermethylated pattern (P < .05). However, on performing binary logistic regression, neither the slow acetylation, intermediate acetylation nor rapid acetylation were found to be associated with ATLI (P > .05). It was found that the total methylation of NAT2 gene promoter region was an independent influencing factor of ATLI in Mongolian tuberculosis patients. With the increase of the total methylation level of NAT2 gene promoter region, the risk of ATLI increased gradually. (OR = 8.371, 95% CI: 2.391 ~ 29.315). CpG1, CpG4, CpG9, CpG10 and CpG11.12 were positively correlated with a total methylation level in the ATLI group. WHAT IS NEW AND CONCLUSION The detection rate of ATLI in Mongolian tuberculosis patients was 27.6%, and there were differences in the NAT2 genotypes and acetylated phenotypes. The slow acetylated type was the risk factor for ATLI. Methylation in the promoter region of the NAT2 gene has an effect on the risk of ATLI. After adjusting for the interference of three acetylation types, it was found that the total methylation of the promoter region of NAT2 gene in Mongolian tuberculosis patients is an independent influencing factor of ATLI. Furthermore, there is a moderate to high correlation between some sites and the overall level of methylation.
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Affiliation(s)
- Dong Zhang
- School of Public Health, Baotou Medical College, Baotou, Inner Mongolia, China
| | - Jinqi Hao
- School of Public Health, Baotou Medical College, Baotou, Inner Mongolia, China
| | - Ruili Hou
- School of Public Health, Baotou Medical College, Baotou, Inner Mongolia, China
| | - Yanqin Yu
- School of Public Health, Baotou Medical College, Baotou, Inner Mongolia, China
| | - Baocui Hu
- School of Public Health, Baotou Medical College, Baotou, Inner Mongolia, China
| | - Liqin Wei
- School of Public Health, Baotou Medical College, Baotou, Inner Mongolia, China
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16
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Santos EA, Gonçalves JCS, Fleury MK, Kritski AL, Oliveira MM, Velasque LS, E Silva JRL, Estrela RDCE. Relationship of anti-tuberculosis drug-induced liver injury and genetic polymorphisms in CYP2E1 and GST. Braz J Infect Dis 2019; 23:381-387. [PMID: 31697922 PMCID: PMC9428211 DOI: 10.1016/j.bjid.2019.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 09/03/2019] [Accepted: 09/06/2019] [Indexed: 02/06/2023] Open
Abstract
SETTING Treatment of tuberculosis (TB) can result in Drug-Induced Liver Injury (DILI) since hepatotoxic metabolites are formed during the biotransformation of isoniazid (INH). DILI can be related to the genetic profile of the patient. Single nucleotide polymorphisms in the CYP2E1 gene and GSTM1 and GSTT1 deletion polymorphisms have been associated with adverse events caused by INH. OBJECTIVE To characterize the genetic polymorphisms of CYP2E1, GSTT1 and GSTM1 in TB carriers. DESIGN This is an observational prospective cohort study of 45 patients undergoing treatment of TB. PCR-RFLP and multiplex-PCR were used. RESULTS The distribution of genotypic frequency in the promoter region (CYP2E1 gene) was: 98% wild genotype and 2% heterozygous. Intronic region: 78% wild genotype; 20% heterozygous and 2% homozygous variant. GST enzyme genes: 24% Null GSTM1 and 22% Null GSTT1. Patients with any variant allele of the CYP2E1 gene were grouped in the statistical analyses. CONCLUSION Patients with the CYP2E1 variant genotype or Null GSTT1 showed higher risk of presenting DILI (p=0.09; OR: 4.57; 95% CI: 0.75-27.6). Individuals with both genotypes had no increased risk compared to individuals with one genotype.
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Affiliation(s)
- Eliana Abreu Santos
- Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Departamento de Fármacos e Medicamentos, Rio de Janeiro, RJ, Brazil.
| | - José Carlos Saraiva Gonçalves
- Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Departamento de Fármacos e Medicamentos, Rio de Janeiro, RJ, Brazil
| | - Marcos K Fleury
- Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Departamento de Análises Clínicas e Toxicológicas, Rio de Janeiro, RJ, Brazil
| | - Afrânio L Kritski
- Universidade Federal do Rio de Janeiro, Instituto de Doenças do Tórax, Rio de Janeiro, RJ, Brazil; Universidade Federal do Rio de Janeiro, Faculdade de Medicina, Programa Acadêmico de Tuberculose, Rio de Janeiro, RJ, Brazil
| | - Martha M Oliveira
- Fundação Oswaldo Cruz, Centro de Desenvolvimento Tecnológico em Saúde, Rio de Janeiro, RJ, Brazil
| | - Luciane S Velasque
- Universidade Federal do Estado do Rio de Janeiro, Departamento de Matemática e Estatística, Rio de Janeiro, RJ, Brazil
| | - José Roberto Lapa E Silva
- Universidade Federal do Rio de Janeiro, Instituto de Doenças do Tórax, Rio de Janeiro, RJ, Brazil; Universidade Federal do Rio de Janeiro, Faculdade de Medicina, Programa Acadêmico de Tuberculose, Rio de Janeiro, RJ, Brazil
| | - Rita de Cássia E Estrela
- Universidade Federal do Rio de Janeiro, Faculdade de Farmácia, Departamento de Fármacos e Medicamentos, Rio de Janeiro, RJ, Brazil; Fundação Oswaldo Cruz, Instituto Nacional de Doenças Infecciosas Evandro Chagas, Laboratório de Pesquisa Clínica em DST/AIDS, Rio de Janeiro, RJ, Brazil
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17
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Yang S, Hwang SJ, Park JY, Chung EK, Lee JI. Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis. BMJ Open 2019; 9:e027940. [PMID: 31375612 PMCID: PMC6688699 DOI: 10.1136/bmjopen-2018-027940] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
OBJECTIVES The objective of this study was to investigate the association between genetic polymorphisms of N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase (GST) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) and the risk of anti-tuberculosis drug-induced liver injury (ATDILI). DESIGN Systematic review and meta-analysis. DATA SOURCES PubMed, Embase, Web of Science and Cochrane Reviews databases were searched through April 2019. ELIGIBILITY CRITERIA We included case-control or cohort studies investigating an association between NAT2, CYP2E1, GST or SLCO1B1 polymorphisms and the ATDILI risk in patients with tuberculosis. DATA EXTRACTION AND SYNTHESIS Three authors screened articles, extracted data and assessed study quality. The strength of association was evaluated for each gene using the pooled OR with a 95% CI based on the fixed-effects or random-effects model. Sensitivity analysis was performed to confirm the reliability and robustness of the results. RESULTS Fifty-four studies were included in this analysis (n=26 for CYP2E1, n=35 for NAT2, n=19 for GST, n=4 for SLCO1B1). The risk of ATDILI was significantly increased with the following genotypes: CYP2E1 RsaI/PstI c1/c1 (OR=1.39, 95% CI 1.06 to 1.83), NAT2 slow acetylator (OR=3.30, 95% CI 2.65 to 4.11) and GSTM1 null (OR=1.30, 95% CI 1.12 to 1.52). No significant association with ATDILI was found for the genetic polymorphisms of CYP2E1 DraI, GSTT1, GSTM1/GSTT1, SLCO1B1 388A>G and SLCO1B1 521T>C (p>0.05). CONCLUSIONS ATDILI is more likely to occur in patients with NAT2 slow acetylator genotype, CYP2E1 RsaI/PstI c1/c1 genotype and GSTM1 null genotype. Close monitoring may be warranted for patients with these genotypes.
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Affiliation(s)
- Seungwon Yang
- Department of Pharmacy and Yonsei Institute of Pharmaceutical Science, Yonsei University, Incheon, Republic of Korea
| | - Se Jung Hwang
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Jung Yun Park
- College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - Eun Kyoung Chung
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
- Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Jangik I Lee
- College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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18
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Richardson M, Kirkham J, Dwan K, Sloan DJ, Davies G, Jorgensen AL. NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis. Int J Tuberc Lung Dis 2019; 23:293-305. [PMID: 30871660 PMCID: PMC6421944 DOI: 10.5588/ijtld.18.0324] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 08/08/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Tuberculosis (TB) patients receiving anti-tuberculosis treatment may experience serious adverse drug reactions (ADRs) such as hepatotoxicity. Variants of the N-acetyltransferase 2 (NAT2) gene may increase the risk of experiencing such toxicity events. OBJECTIVE To provide a comprehensive evaluation of the evidence base for associations between NAT2 variants and anti-tuberculosis drug-related toxicity. METHOD This was a systematic review and meta-analysis. We searched for studies in Medline, PubMed, EMBASE, BIOSIS and Web of Science. We included data from 41 articles (39 distinct cohorts of patients). We pooled effect estimates for each genotype on each outcome using meta-analyses stratified by country. RESULTS We assessed the quality of the included studies, which was variable, with many areas of concern. Slow/intermediate NAT2 acetylators were statistically significantly more likely to experience hepatotoxicity than rapid acetylators (OR 1.59, 95%CI 1.26-2.01). Heterogeneity was not detected in the overall pooled analysis (I² = 0%). NAT2 acetylator status was significantly associated with the likelihood of experiencing anti-tuberculosis drug-related hepatotoxicity. CONCLUSION We encountered several challenges in performing robust syntheses of data from pharmacogenetic studies, and we outline recommendations for the future reporting of pharmacogenetic studies to enable high-quality systematic reviews and meta-analyses to be performed.
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Affiliation(s)
- M Richardson
- Department of Biostatistics, University of Liverpool, Liverpool
| | - J Kirkham
- Department of Biostatistics, University of Liverpool, Liverpool
| | - K Dwan
- Cochrane Editorial Unit, London
| | - D J Sloan
- School of Medicine, University of St Andrews, St Andrews
| | - G Davies
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK
| | - A L Jorgensen
- Department of Biostatistics, University of Liverpool, Liverpool
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Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence. Biosci Rep 2019; 39:BSR20180845. [PMID: 30509962 PMCID: PMC6331676 DOI: 10.1042/bsr20180845] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 11/13/2018] [Accepted: 11/27/2018] [Indexed: 01/11/2023] Open
Abstract
Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100–1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137–1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052–1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug–enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.
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Richardson M, Kirkham J, Dwan K, Sloan DJ, Davies G, Jorgensen AL. CYP genetic variants and toxicity related to anti-tubercular agents: a systematic review and meta-analysis. Syst Rev 2018; 7:204. [PMID: 30458875 PMCID: PMC6247669 DOI: 10.1186/s13643-018-0861-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/29/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Treatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes. METHODS We searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies. RESULTS We included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56-1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38-48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19-3.21, I2 = 0%). CONCLUSIONS Generally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants' ethnicity was sparsely reported in the included studies. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number: CRD42017068448.
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Affiliation(s)
- Marty Richardson
- Department of Biostatistics, University of Liverpool, Liverpool, L69 3GB UK
| | - Jamie Kirkham
- Department of Biostatistics, University of Liverpool, Liverpool, L69 3GB UK
| | - Kerry Dwan
- Cochrane Editorial Unit, London, SW1Y 4QX UK
| | - Derek J. Sloan
- School of Medicine, University of St Andrews, St Andrews, KY16 9TF UK
| | - Geraint Davies
- Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, L69 3GB UK
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21
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Zhang M, Wang S, Wilffert B, Tong R, van Soolingen D, van den Hof S, Alffenaar JW. The association between the NAT2 genetic polymorphisms and risk of DILI during anti-TB treatment: a systematic review and meta-analysis. Br J Clin Pharmacol 2018; 84:2747-2760. [PMID: 30047605 PMCID: PMC6256008 DOI: 10.1111/bcp.13722] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 07/11/2018] [Accepted: 07/20/2018] [Indexed: 12/13/2022] Open
Abstract
AIMS The aim of this study is to evaluate the potential association between N-acetyltransferase type 2 (NAT2) polymorphisms and drug-induced liver injury during anti-TB treatment (AT-DILI). METHODS We conducted a systematic review and performed a meta-analysis to clarify the role of NAT2 polymorphism in AT-DILI. PubMed, Medline and EMBASE databases were searched for studies published in English to December 31, 2017, on the association between the NAT2 polymorphism and AT-DILI risk. Outcomes were pooled with random-effects meta-analysis. Details were registered in the PROSPERO register (number: CRD42016051722). RESULTS Thirty-seven studies involving 1527 cases and 7184 controls were included in this meta-analysis. The overall odds ratio (OR) of AT-DILI associated with NAT2 slow acetylator phenotype was 3.15 (95% CI 2.58-3.84, I2 = 51.3%, P = 0.000). The OR varied between different ethnic populations, ranging from 6.42 (95% CI 2.41-17.10, I2 = 2.3%) for the West Asian population to 2.32 (95% CI 0.58-9.24, I2 = 80.3%) for the European population. Within the slow NAT2 genotype, variation was also observed; NAT2*6/*7 was associated with the highest risk of AT-DILI (OR = 1.68, 95% CI 1.09-2.59) compared to the other slow NAT2 acetylators combined. CONCLUSIONS NAT2 slow acetylation was observed to increase the risk of AT-DILI in tuberculosis patients. Our results support the hypothesis that the slow NAT2 genotype is a risk factor for AT-DILI.
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Affiliation(s)
- Min Zhang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.,University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
| | - Shuqiang Wang
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.,Department of Infectious Diseases, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China
| | - Bob Wilffert
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.,Department of Pharmacotherapy, -Epidemiology, & -Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Rongsheng Tong
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.,Personalized Drug Therapy Key Laboratory of Sichuan Province
| | - Dick van Soolingen
- Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.,Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | | | - Jan-Willem Alffenaar
- University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands
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22
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NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury. Pharmacogenet Genomics 2018; 28:167-176. [DOI: 10.1097/fpc.0000000000000339] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Effect of gene-gene and gene-environment interactions associated with antituberculosis drug-induced hepatotoxicity. Pharmacogenet Genomics 2018; 27:363-371. [PMID: 28799976 DOI: 10.1097/fpc.0000000000000300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVES This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires. PATIENTS AND METHODS We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH. RESULTS This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P<0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P=0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P=0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P=0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P<0.001). We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy=0.675 (P=0.001) and cross-validation consistency=10/10]. CONCLUSION ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB patients. Our study created a prediction model that properly classified the 67.5% of TB patients in their risk of developing ATDH. The considerable number of TB patients in our country supports the use of pharmacogenetic testing and a comprehensive clinical history to identify patients with a high risk of suffering hepatotoxicity.
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25
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Chan SL, Chua APG, Aminkeng F, Chee CBE, Jin S, Loh M, Gan SH, Wang YT, Brunham LR. Association and clinical utility of NAT2 in the prediction of isoniazid-induced liver injury in Singaporean patients. PLoS One 2017; 12:e0186200. [PMID: 29036176 PMCID: PMC5642896 DOI: 10.1371/journal.pone.0186200] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Accepted: 09/27/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIMS Isoniazid (INH) is part of the first-line-therapy for tuberculosis (TB) but can cause drug-induced liver injury (DILI). Several candidate single nucleotide polymorphisms (SNPs) have been previously identified but the clinical utility of these SNPs in the prediction of INH-DILI remains uncertain. The aim of this study was to assess the association between selected candidate SNPs and the risk of INH-DILI and to assess the clinical validity of associated variants in a Singaporean population. METHODS This was a case-control study where 24 INH-DILI cases and 79 controls were recruited from the TB control unit in a tertiary hospital. Logistic regression was used to test for the association between candidate SNPs and INH-DILI. NAT2 acetylator status was inferred from genotypes and tested for association with INH-DILI. Finally, clinical validity measures were estimated for significant variants. RESULTS Two SNPs in NAT2 (rs1041983 and rs1495741) and NAT2 slow acetylators (SA) were significantly associated with INH-DILI (OR (95% CI) = 13.86 (4.30-44.70), 0.10 (0.03-0.33) and 9.98 (3.32-33.80), respectively). Based on an INH-DILI prevalence of 10%, the sensitivity, specificity, positive and negative predictive values of NAT2 SA were 75%, 78%, 28% and 97%, respectively. The population attributable fraction (PAF) and number needed to test (NNT) for NAT2 SA were estimated to be 0.67 and 4.08, respectively. A model with clinical and NAT2 acetylator status provided significantly better prediction for INH-DILI than a clinical model alone (area under receiver operating characteristic curve = 0.863 vs. 0.766, respectively, p = 0.027). CONCLUSIONS We show the association between NAT2 SA and INH-DILI in a Singaporean population and demonstrated its clinical utility in the prediction of INH-DILI.
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Affiliation(s)
- Sze Ling Chan
- Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore and the National University of Singapore, Singapore
| | | | - Folefac Aminkeng
- Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore and the National University of Singapore, Singapore
| | | | - Shengnan Jin
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Marie Loh
- Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore and the National University of Singapore, Singapore
| | - Suay Hong Gan
- Department of Respiratory Medicine, Tan Tock Seng Hospital, Singapore
| | - Yee Tang Wang
- Department of Respiratory Medicine, Tan Tock Seng Hospital, Singapore
| | - Liam R. Brunham
- Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore and the National University of Singapore, Singapore
- Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada
- * E-mail:
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McMullan GS, Lewis JH. Tuberculosis of the Liver, Biliary Tract, and Pancreas. Microbiol Spectr 2017; 5:10.1128/microbiolspec.tnmi7-0025-2016. [PMID: 28233514 PMCID: PMC11687442 DOI: 10.1128/microbiolspec.tnmi7-0025-2016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Indexed: 12/13/2022] Open
Abstract
Tuberculosis of the liver, biliary tract, and pancreas is discussed. In addition, tuberculosis in the setting of HIV-AIDS and liver transplantation is explored. Drug-induced liver injury secondary to antituberculosis medication and monitoring and prophylactic treatment for such injury is also considered.
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Affiliation(s)
- G Shelton McMullan
- Division of Gastroenterology, Georgetown University Hospital, Washington, DC 20007
| | - James H Lewis
- Division of Hepatology, Department of Medicine, Georgetown University Hospital, Washington, DC 20007
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27
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Heinrich MM, Zembrzuski VM, Ota MM, Sacchi FP, Teixeira RL, Cabello Acero PH, Cunha GM, Souza-Santos R, Croda J, Basta PC. Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil. Tuberculosis (Edinb) 2016; 101:15-24. [DOI: 10.1016/j.tube.2016.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 06/26/2016] [Accepted: 07/10/2016] [Indexed: 12/18/2022]
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Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment. Antimicrob Agents Chemother 2016; 60:5285-93. [PMID: 27324775 DOI: 10.1128/aac.00854-16] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 06/11/2016] [Indexed: 12/22/2022] Open
Abstract
Isoniazid (INH) remains the core drug in tuberculosis management, but serious hepatotoxicity and potentially fatal liver injury continue to accompany INH consumption. Among numerous theories that have been established to explain INH-induced liver injury, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. Inflammatory stress usually sensitizes tissues to a drug's toxic consequences. Therefore, the present study was conducted to verify whether bacterial lipopolysaccharide (LPS)-induced inflammation may have a role in enhancing INH hepatotoxicity. While single INH or LPS administration showed no major toxicity signs, INH-LPS cotreatment intensified liver toxicity. Both blood biomarkers and histological evaluations clearly showed positive signs of severe liver damage accompanied by massive necrosis, inflammatory infiltration, and hepatic steatosis. Furthermore, elevated serum levels of bile acid associated with the repression of bile acid synthesis and transport regulatory parameters were observed. Moreover, the principal impact of cytochrome P450 2E1 (CYP2E1) on INH toxicity could be anticipated, as its protein expression showed enormous increases in INH-LPS-cotreated animals. Furthermore, the crucial role of CYP2E1 in the production of reactive oxygen species (ROS) was clearly obvious in the repression of hepatic antioxidant parameters. In summary, these results confirmed that this LPS-induced inflammation model might prove valuable in revealing the hepatotoxic mechanisms of INH and the crucial role played by CYP2E1 in the initiation and propagation of INH-induced liver damage, information which could be very useful to clinicians in understanding the pathogenesis of drug-induced liver injury.
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Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS. PLoS One 2016; 11:e0157725. [PMID: 27332812 PMCID: PMC4917242 DOI: 10.1371/journal.pone.0157725] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 06/04/2016] [Indexed: 11/24/2022] Open
Abstract
Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA.
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30
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Yang Y, Jiang L, Wang S, Zeng T, Xie K. Diallyl trisulfide protects the liver against hepatotoxicity induced by isoniazid and rifampin in mice by reducing oxidative stress and activating Kupffer cells. Toxicol Res (Camb) 2016; 5:954-962. [PMID: 30090404 PMCID: PMC6060719 DOI: 10.1039/c5tx00440c] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 03/25/2016] [Indexed: 11/21/2022] Open
Abstract
Background & Aim: Diallyl trisulfide (DATS) has been verified to ameliorate hepatotoxicity induced by many drugs, but the protective actions of isoniazid (INH) and rifampicin (RFP) have not been reported. We attempted to elucidate the potential effects and mechanisms of DATS against INH&RFP-caused hepatotoxicity. Methods: Male Kunming mice weighing 18-22 g were divided into 6 groups. For the hepatic-protective study, DATS (10 mg per kg, 20 mg per kg, and 40 mg per kg bw, respectively) was orally administered two hours before the INH&RFP (100 mg per kg, 100 mg per kg bw, respectively) treatments. After 11 days of treatment, 10 mice in each group were taken for the carbon clearance test, while the other 10 mice were sacrificed for the collection of serum and livers for further measurements, including the levels of serum alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (T.Bili), the liver index, and liver histopathological examination. Malondialdehyde (MDA), glutathione (GSH), and the level of interleukin 1-β (IL-1-β) were measured, the carbon clearance test was performed and the immunohistochemistry of F4/80 marker for activated Kupffer cells (KCs) was analyzed to investigate potential mechanisms. Results: DATS co-administration significantly inhibited the increase of liver index and elevation of serum ALT, AST and T.Bili levels induced by INH&RFP, as well as improved the hepatocellular structure. The further mechanistic studies demonstrated that DATS co-administration counteracted INH&RFP-induced oxidative stress in mice, which was illustrated by the restoration of GSH levels, and the reduction of MDA levels in the liver. Furthermore, DATS co-administration reactivated the KCs inhibited by INH&RFP, which was illustrated by the increase of carbon phagocytosis, and the restoration of the number of activated KCs and IL-1-β levels in the liver. Conclusion: DATS effectively protected the liver against INH&RFP-induced hepatotoxicity, which might be due to its antioxidant effect and enhancement of KCs' activities.
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Affiliation(s)
- Yilin Yang
- Institute of Toxicology , School of Public Health , Shandong University , 44 West Wenhua Road , Jinan 250012 , P.R. China . ; ; ; ; Tel: +86-531-8838-2132
| | - Lulu Jiang
- Institute of Toxicology , School of Public Health , Shandong University , 44 West Wenhua Road , Jinan 250012 , P.R. China . ; ; ; ; Tel: +86-531-8838-2132
| | - Shuo Wang
- Institute of Toxicology , School of Public Health , Shandong University , 44 West Wenhua Road , Jinan 250012 , P.R. China . ; ; ; ; Tel: +86-531-8838-2132
| | - Tao Zeng
- Institute of Toxicology , School of Public Health , Shandong University , 44 West Wenhua Road , Jinan 250012 , P.R. China . ; ; ; ; Tel: +86-531-8838-2132
| | - Keqin Xie
- Institute of Toxicology , School of Public Health , Shandong University , 44 West Wenhua Road , Jinan 250012 , P.R. China . ; ; ; ; Tel: +86-531-8838-2132
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Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients. THE PHARMACOGENOMICS JOURNAL 2016; 17:372-377. [PMID: 27089936 DOI: 10.1038/tpj.2016.26] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 02/06/2016] [Accepted: 02/26/2016] [Indexed: 02/06/2023]
Abstract
Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l-1 (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l-1 remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l-1 and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.
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Wang FJ, Wang Y, Niu T, Lu WX, Sandford AJ, He JQ. Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies. J Clin Pharm Ther 2016; 41:334-40. [PMID: 27062377 DOI: 10.1111/jcpt.12388] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 03/14/2016] [Indexed: 02/05/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE Several studies have investigated the association of the CYP2E1 RsaI/PstI and/or DraI polymorphisms with susceptibility to antituberculosis drug-induced hepatotoxicity (ATDH), but the results have been inconsistent. Therefore, we performed a large meta-analysis to determine a more precise estimation of this relationship. METHODS The PubMed, EMBASE, China National Knowledge Infrastructure and Chinese Biomedical Literature databases were systematically searched to identify relevant studies. Meta-analyses based on the entire population and subgroups were performed to examine the association between CYP2E1 polymorphisms and susceptibility to ATDH. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the associations. RESULTS AND DISCUSSION Twenty-six studies with a total of 7423 participants were analysed. The overall ORs of relevant studies demonstrated that the CYP2E1 RsaI/PstI C1/C1 genotype was associated with an elevated risk of ATDH (OR = 1·32, 95% CI 1·03-1·69, P = 0·027), but for the DraI polymorphism there was no increase in risk (OR = 1·05, 95% CI 0·80-1·37, P = 0·748). In subgroup analyses of the RsaI/PstI polymorphism, significant results were found in East Asians, patients who used isoniazid + rifampicin + pyrazinamide + ethambutol and patients with twice the upper limit of normal as the minimum standard for defining ATDH. WHAT IS NEW AND CONCLUSION This meta-analysis suggests that there is an increased risk of ATDH in individuals carrying the C1/C1 genotype of the CYP2E1 RsaI/PstI polymorphism. However, no association was found for the DraI polymorphism.
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Affiliation(s)
- F-J Wang
- Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Y Wang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - T Niu
- Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - W-X Lu
- West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
| | - A J Sandford
- Centre for Heart Lung Innovation, University of British Columbia and St. Paul's Hospital, Vancouver, BC, Canada
| | - J-Q He
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Cojutti P, Duranti S, Isola M, Baraldo M, Viale P, Bassetti M, Pea F. Might isoniazid plasma exposure be a valuable predictor of drug-related hepatotoxicity risk among adult patients with TB? J Antimicrob Chemother 2016; 71:1323-9. [PMID: 26832752 DOI: 10.1093/jac/dkv490] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 12/18/2015] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES To investigate the relationship between isoniazid plasma exposure and the likelihood of elevation of ALT (≥51 IU/L) among adult patients with TB. METHODS A retrospective observational study was conducted in patients who underwent periodic monitoring of hepatic function and in whom pharmacokinetic data were collected. Monte Carlo simulation was performed with the intent of identifying the probability of achieving an AUC24 greater than the identified threshold of hepatotoxicity with different dosing regimens (2.5, 5.0 and 7.5 mg/kg/day). RESULTS Forty-one out of 185 evaluable patients (22.2%) had an ALT elevation. A mild correlation between isoniazid AUC0-24 and ALT increase was observed (Spearman's ρ = 0.34, P < 0.001). Patients with ALT ≥51 IU/L showed significantly higher isoniazid exposure than those with ALT <51 IU/L (mean AUC24 of 58.33 versus 31.28 mg·h/L, P < 0.001). The probabilities of ALT elevation were 0.82 and 0.12 for isoniazid AUC24 ≥55.0 and <55.0 mg·h/L, respectively. Use of a logistic regression model estimated a likelihood of developing hepatotoxicity of 0.5 and 0.9 when in the presence of an isoniazid AUC24 of 53.7 and 70.0 mg·h/L, respectively. Simulation showed that the standard isoniazid 5 mg/kg daily dose gave a probability of ALT increase of 0.46 for slow acetylators and 0.03 for rapid acetylators. CONCLUSIONS Plasma isoniazid exposure might be a valuable predictor of drug-related hepatotoxicity. Early assessment of isoniazid exposure at the beginning of treatment might allow prompt dosage reduction among those patients who are experiencing drug overexposure, thus containing the risk of hepatotoxicity occurrence.
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Affiliation(s)
- Piergiorgio Cojutti
- Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
| | - Silvia Duranti
- Infectious Diseases Division, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy
| | - Miriam Isola
- Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy
| | - Massimo Baraldo
- Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
| | - Pierluigi Viale
- Infectious Diseases Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Matteo Bassetti
- Infectious Diseases Division, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy
| | - Federico Pea
- Institute of Clinical Pharmacology, Azienda Ospedaliero-Universitaria Santa Maria della Misericordia, Udine, Italy Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy
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Shi J, Xie M, Wang J, Xu Y, Liu X. Susceptibility of N-acetyltransferase 2 slow acetylators to antituberculosis drug-induced liver injury: a meta-analysis. Pharmacogenomics 2015; 16:2083-97. [PMID: 26616266 DOI: 10.2217/pgs.15.144] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM This study aimed to evaluate the association between N-acetyltransferase 2 (NAT2) gene polymorphisms and the risk of antituberculosis drug-induced liver injury (ATLI). MATERIALS & METHODS A meta-analysis was performed including 27 studies with 1289 cases and 5462 controls. Odds ratio with 95% CI was used to evaluate the strength of association. RESULTS Our meta-analysis found that NAT2 slow acetylators were associated with increased risk of ATLI compared with fast and intermediate acetylators when standard dose of isoniazid was administrated (odds ratio: 3.08; 95% CI: 2.29-4.15). CONCLUSION Individuals with NAT2 slow acetylators may have increased risk of ATLI when standard dose of isoniazid was used. Detection of NAT2 genotype may benefit to the prevention of ATLI.
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Affiliation(s)
- Jing Shi
- Department of Respiration & Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Min Xie
- Department of Respiration & Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Jianmiao Wang
- Department of Respiration & Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Yongjian Xu
- Department of Respiration & Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Xiansheng Liu
- Department of Respiration & Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
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Bisso-Machado R, Ramallo V, Paixão-Côrtes VR, Acuña-Alonzo V, Demarchi DA, Sandoval JRS, Granara AAS, Salzano FM, Hünemeier T, Bortolini MC. NAT2 gene diversity and its evolutionary trajectory in the Americas. THE PHARMACOGENOMICS JOURNAL 2015; 16:559-565. [DOI: 10.1038/tpj.2015.72] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 08/21/2015] [Accepted: 09/08/2015] [Indexed: 01/26/2023]
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Hassan HM, Guo HL, Yousef BA, Luyong Z, Zhenzhou J. Hepatotoxicity mechanisms of isoniazid: A mini-review. J Appl Toxicol 2015; 35:1427-32. [DOI: 10.1002/jat.3175] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 04/17/2015] [Indexed: 12/25/2022]
Affiliation(s)
- Hozeifa M. Hassan
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Department of Pharmacology, Faculty of Pharmacy; University of Gezira; Wad-Medani Sudan
| | - Hong-li Guo
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
| | - Bashir A. Yousef
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Department of Pharmacology, Faculty of Pharmacy; University of Khartoum; Khartoum Sudan
| | - Zhang Luyong
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Jiangsu Center for Pharmacodynamics Research and Evaluation; China Pharmaceutical University; Nanjing China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research; China Pharmaceutical University; Nanjing China
| | - Jiang Zhenzhou
- Jiangsu Key Laboratory of Drug Screening; China Pharmaceutical University; Nanjing China
- Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University); Ministry of Education; Nanjing China
- State Key Laboratory of Natural Medicines; China Pharmaceutical University; Nanjing China
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Shayakhmetova GM, Bondarenko LB, Voronina AK, Anisimova SI, Matvienko AV, Kovalenko VM. Induction of CYP2E1 in testes of isoniazid-treated rats as possible cause of testicular disorders. Toxicol Lett 2015; 234:59-66. [DOI: 10.1016/j.toxlet.2015.02.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 02/02/2015] [Accepted: 02/11/2015] [Indexed: 12/16/2022]
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Fernandes DCRO, Santos NPC, Moraes MR, Braga ACO, Silva CA, Ribeiro-dos-Santos A, Santos S. Association of the CYP2B6 gene with anti-tuberculosis drug-induced hepatotoxicity in a Brazilian Amazon population. Int J Infect Dis 2014; 33:28-31. [PMID: 25271170 DOI: 10.1016/j.ijid.2014.04.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 04/01/2014] [Accepted: 04/12/2014] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES The treatment of tuberculosis (TB) remains a challenge owing to the high incidence of drug-induced hepatotoxicity. The aim of this study was to examine the effect of two gene polymorphisms, one in the CYP2B6 (rs3745274) gene and one in the CYP3A5 (rs776746) gene, on the development of hepatotoxicity in patients treated with anti-TB drugs in a Brazilian Amazon population. METHODS TB patients who were treated with anti-TB drugs were examined for hepatotoxicity, an adverse effect that is characterized by liver damage. The genotype frequencies of the CYP2B6 and CYP3A5 genes examined in this study were assessed using RT-PCR. RESULTS Thirty-one of the 220 subjects (14.1%) included in this study developed drug-induced hepatotoxicity. The result was significant when the TT homozygous mutant of the CYP2B6 gene was analyzed with additional key variables (p=0.046; odds ratio (OR) 0.063, 95% confidence interval (CI) 0.004-0.955), which may explain the hepatotoxicity results in this study. Using a univariate statistical model to associate the CYP3A5 gene A6986G polymorphism with the examined drugs, the results did not differ between samples from individuals with and without hepatotoxicity (p=0.176; OR 0.562, 95% CI 0.255-1.238). CONCLUSIONS The G516T polymorphism in the CYP2B6 gene is a key predictor of the therapeutic response to treatment in TB patients.
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Affiliation(s)
- Débora Christina Ricardo Oliveira Fernandes
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-970 Belém, Pará, Brazil; Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil
| | - Ney Pereira Carneiro Santos
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-970 Belém, Pará, Brazil; Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil
| | - Milene Raiol Moraes
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-970 Belém, Pará, Brazil
| | | | | | - Andrea Ribeiro-dos-Santos
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-970 Belém, Pará, Brazil; Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil
| | - Sidney Santos
- Laboratório de Genética Humana e Médica, Instituto de Ciências Biológicas, Universidade Federal do Pará, CEP 66075-970 Belém, Pará, Brazil; Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Pará, Brazil.
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PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2. Pharmacogenet Genomics 2014; 24:409-25. [PMID: 24892773 DOI: 10.1097/fpc.0000000000000062] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Ng CS, Hasnat A, Al Maruf A, Ahmed MU, Pirmohamed M, Day CP, Aithal GP, Daly AK. N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group. Eur J Clin Pharmacol 2014; 70:1079-86. [PMID: 24888881 DOI: 10.1007/s00228-014-1703-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 05/22/2014] [Indexed: 12/16/2022]
Abstract
PURPOSE This study aims to assess whether NAT2 genotype affects susceptibility to moderate to severe liver injury in patients undergoing drug treatment for tuberculosis with isoniazid-containing regimens. METHODS Twenty-six patients of European or South Asian ethnicity, who had suffered liver injury during treatment with isoniazid-containing drug regimens and 101 ethnically matched controls were genotyped for the NAT2*5, NAT2*6, and NAT2*7 alleles. Genotyping for additional polymorphisms in the NAT gene region was also performed on 20 of the 26 cases. NAT2 genotype frequency between cases and controls was compared. RESULTS NAT2 genotypes predicting a slow acetylator phenotype were found to be associated with an increased risk of isoniazid-related liver injury (odds ratio (OR) = 4.25 (95% confidence interval (CI), 1.36-13.22); p = 0.012) with 85% of the cases being slow acetylators compared with 56% of the controls. There was no evidence for an increased risk for the slow acetylator genotype in patients with the most severe cases of liver injury, who underwent liver transplantation. CONCLUSIONS The NAT2 slow acetylator genotype appears to be a significant risk factor for moderate and severe drug- induced liver injury. However, the overall effect size is modest and generally in line with effects described previously for this genotype in milder drug-induced liver injury. Additional genetic risk factors may also contribute.
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Affiliation(s)
- Ching-Soon Ng
- Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
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Zaverucha-do-Valle C, Monteiro SP, El-Jaick KB, Rosadas LA, Costa MJM, Quintana MSB, de Castro L. The role of cigarette smoking and liver enzymes polymorphisms in anti-tuberculosis drug-induced hepatotoxicity in Brazilian patients. Tuberculosis (Edinb) 2014; 94:299-305. [PMID: 24793319 DOI: 10.1016/j.tube.2014.03.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 03/20/2014] [Indexed: 12/13/2022]
Abstract
Tuberculosis (TB) is still a major health concern and side-effects related to the treatment, especially drug-induced hepatotoxicity (DIH), should be better investigated. In the present study, a possible association between anti-TB DIH and cigarette smoking, N-acetyltransferase 2 (NAT2), Cytochrome P450 2E1 (CYP2E1) and Cytochrome P450 3A4 (CYP3A4) genotypes was studied in 131 TB Brazilian patients. The NAT2 and CYP3A4 genetic polymorphisms were determined using a polymerase chain reaction (PCR) direct sequencing approach and genetic polymorphisms of CYP2E1 gene were determined by restriction fragment length polymorphism (RFLP). The risk of anti-TB DIH was lower in rapid/intermediate acetylators when compared to slow acetylators (OR: 0.34, CI 95: 0.16-0.71; p < 0.01). A decreased risk of developing anti-TB DIH was also observed in active smokers when compared to non-smokers (OR: 0.28, 95 CI: 0.11-0.64; p < 0.01). Significant association between CYP3A4 genotypes and hepatotoxicity was not observed, as well as between CYP2E1 genotype and hepatotoxicity, whose frequency of patients with wild homozygous was more prevalent. The anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require to adjust therapeutic regimen dosages or alarm in case of adverse event developments.
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Affiliation(s)
- Camila Zaverucha-do-Valle
- Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Sérgio P Monteiro
- Human Genetic Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Kênia B El-Jaick
- Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; Genetics and Molecular Biology Department of Federal University of Rio de Janeiro State, Brazil
| | - Leonardo A Rosadas
- Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Marli J M Costa
- Tuberculosis and Mycobacteria Clinical Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Marcel S B Quintana
- Technical Assistance of Clinical Research and Reference Services, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Liane de Castro
- Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
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Singla N, Gupta D, Birbian N, Singh J. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis (Edinb) 2014; 94:293-8. [PMID: 24637014 DOI: 10.1016/j.tube.2014.02.003] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 02/05/2014] [Accepted: 02/06/2014] [Indexed: 01/07/2023]
Abstract
Adherence to the prescribed anti-tuberculosis drug (ATD) treatment is crucial for curing patients with active TB. Anti-tuberculosis drug (ATD) induced hepatotoxicity (ATDH) may contribute to ATD's poor compliance in patients with tuberculosis (TB) as interruption of treatment and the switch to second-line anti-tuberculosis drugs, which is required in patients who do not tolerate standard drugs, may result in a sub-optimal treatment response. Isoniazid (INH) is a part of ATD and involved with ATDH due to toxic metabolites produced on its metabolism in liver, attributed to the variation in enzymes involved in this pathway like N-acetyltransferase 2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferases (GSTs). The present study aimed at analysis of polymorphism at three loci of NAT2, two loci of GST and one locus on CYP2E1 and development of ATDH in patients undergoing ATD therapy. A total of 408 newly diagnosed patients with tuberculosis were enrolled for this study and at the end of sampling, 17 ATDH cases and 391 non-ATDH cases were reported. The genetic polymorphisms of the NAT2 and CYP2E1 genes were studied by PCR-RFLP and GSTM1 and GSTT1 were evaluated by multiplex PCR. Slow phenotype of NAT2 was found to be a risk factor for developing ATDH when compared to fast acetylators. Slow haplotype C481A590G857 and an intermediate acetylator haplotype T481A590G857 were found to be significantly associated with development of ATDH. GSTM1 and GSTT1 double null genotype was also reported to be associated with ATDH development. The heterozygote genotype 'c1c2' of CYP2E1 was also seen to contribute towards elevated risk of ATDH. 'c2' allele absence in females ATDH group can be considered as a protective factor against development of ATDH. In males, presence of 'c1c2' allele was seen to contribute towards elevated risk of ATDH development.
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Affiliation(s)
- Neha Singla
- Department of Biotechnology, Panjab University, Chandigarh 160014, India.
| | - Dheeraj Gupta
- Department of Pulmonary Medicine, PGIMER, Chandigarh 160012, India.
| | - Niti Birbian
- Department of Biotechnology, Panjab University, Chandigarh 160014, India.
| | - Jagtar Singh
- Department of Biotechnology, Panjab University, Chandigarh 160014, India.
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Selinski S, Blaszkewicz M, Ickstadt K, Hengstler JG, Golka K. Refinement of the prediction of N-acetyltransferase 2 (NAT2) phenotypes with respect to enzyme activity and urinary bladder cancer risk. Arch Toxicol 2013; 87:2129-39. [DOI: 10.1007/s00204-013-1157-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 10/30/2013] [Indexed: 01/26/2023]
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