Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity

Yew, Wing Wai; Chang, Kwok Chiu; Chan, David Yiu Leung

doi:10.1128/aac.02637-17

Cited by 58 publications

(52 citation statements)

References 72 publications

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“…Additionally, plasma specimens collected at different time points during treatment from each patient are also important for ADR studies. Previous studies have shown that oxidative stress, and more broadly, disturbances in redox homeostasis alongside mitochondrial dysfunction, may contribute to the hepatotoxicity induced by first-line anti-TB drugs 49. A rat study suggested that INH may initiate its toxicity in liver mitochondria through interactions with electron transfer chains, lipid peroxidation, mitochondrial membrane potential decline and cytochrome c expulsion, which ultimately leads to cell death 50.…”

Section: Discussionmentioning

confidence: 99%

Home-based Anti-Tuberculosis Treatment Adverse Reactions (HATTAR) study: a protocol for a prospective observational study

Yang

Pan

et al. 2019

BMJ Open

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IntroductionTuberculosis (TB) continues to be an important public health problem throughout much of the world. Drug treatment is the only effective treatment method, but adverse drug events (ADEs) and adverse drug reactions (ADRs) can affect medication adherence. As the number of drug-resistant TB patients and the number of anti-TB drugs have increased, it is necessary to explore the risk factors for ADEs/ADRs to reduce their occurrence. This study aims to build a home-based anti-TB treatment cohort and to recognise the incidences, prognosis and risk factors of anti-TB drug-induced ADEs/ADRs in real-world experiences.Methods and analysisThis study is a multicentre, prospective observational cohort study. The study population will consist of 3200 newly diagnosed TB patients between January 2019 and December 2020. After initiating the anti-TB treatment, all patients will be followed up until finishing treatment unless they withdraw, and we will record personal drug use and signs and/or symptoms of discomfort. Patients will receive scheduled laboratory tests in designated hospitals every 2 weeks during the first 2 months, and the residual blood sample after conducting the laboratory tests will be preserved. The ADEs/ADRs will be placed into eight categories: liver dysfunction, gastrointestinal reactions, drug allergy, arthralgia or muscle pain, nervous system disorders, haematological system disorders, renal impairment and others.Ethics and disseminationThis study protocol has been approved by the ethics committees of Nanjing Medical University. All patients will give written informed consent before enrollment. The findings of the study will be published in peer-reviewed journals and will be presented at national and international conferences.

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Section: Discussionmentioning

confidence: 99%

Home-based Anti-Tuberculosis Treatment Adverse Reactions (HATTAR) study: a protocol for a prospective observational study

Yang

Pan

et al. 2019

BMJ Open

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“…A recent study showed that INH could induce ROS levels and apoptosis in both HepG2 and THLE‐2 cells, and the expression of apoptotic and antioxidative genes was shown to increase . Experimental and clinical studies indicated that oxidative stress, resulting from abnormal ROS accumulation, plays an important role in ATLI …”

Section: What Is Known and Objectivementioning

confidence: 99%

“…9 Experimental and clinical studies indicated that oxidative stress, resulting from abnormal ROS accumulation, plays an important role in ATLI. 10 Nuclear factor erythroid 2-related factor 2 (Nrf2) and its endogenous inhibitor kelch-like ECH associating protein 1 (Keap1) function as a ubiquitous, evolutionarily conserved intracellular defense mechanism to counteract oxidative stress. 11 Oxidative stress causes Nrf2 to detach from Keap1 and translocate to the nucleus, wherein it heterodimerizes with small musculoaponeurotic fibrosarcoma proteins.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

Possible association of HMOX1 and NQO1 polymorphisms with anti-tuberculosis drug-induced liver injury: A matched case-control study

et al. 2019

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Summary What is known and objective Reactive metabolites from anti‐tuberculosis (anti‐TB) drugs can result in abnormal accumulation of reactive oxygen species (ROS), which plays an important role in anti‐TB drug‐induced liver injury (ATLI). Liver cells could keep the production of ROS in balance by antioxidant activities. The heme oxygenase 1, encoded by the HMOX1 gene and NADH:quinone oxidoreductase 1, encoded by the NQO1 gene are crucial mediators of cellular defense against ROS. The present study aimed to investigate the associations between HMOX1 and NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Methods A matched case‐control study was conducted using 314 ATLI cases and 628 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATLI by the odds ratios (ORs) with 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. Results and discussion Patients carrying the GG genotype at rs2071748 in HMOX1 were at a higher risk of ATLI than those with the AA genotype (adjusted OR = 1.503, 95% CI: 1.005‐2.249, P = 0.047), and significant differences were also found under the recessive (P = 0.015) and additive (P = 0.045) models. Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the recessive and additive models (adjusted OR = 1.714, 95% CI: 1.169‐2.513, P = 0.006; adjusted OR = 1.287, 95% CI: 1.015‐1.631, P = 0.037, respectively). What is new and conclusion This is the first study to explore the relationship between HMOX1, NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Based on a matched case‐control study, genetic polymorphisms of HMOX1 may be associated with susceptibility to ATLI in the Chinese population.

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“…https://doi.org/10.1101/2020.04. 14.20065292 doi: medRxiv preprint for toxicity prevention 13 . Here, we hypothesized that long-term exposures to isoniazid and its metabolites were related to markers of redox imbalance in hepatocytes, and that hydrazine exposures would drive redox imbalance and oxidative damage in the liver.…”

Section: Introductionmentioning

confidence: 99%

Redox imbalance and oxidative DNA damage during isoniazid treatment: A clinical and translational pharmacokinetic study

Zentner¹,

Back

Kagan

et al. 2020

Preprint

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Background: The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage. Methods: We performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylisoniazid, hydrazine, and acetylhydrazine. Physiologically-based pharmacokinetic modeling was used to estimate liver tissue exposures during a 24-hour dosing interval for each compound. We experimentally treated HepG2 cells with isoniazid and metabolites at equimolar concentrations corresponding to these exposures for 7, 14, and 28 day periods, and performed assays related to redox imbalance and oxidative DNA damage at each timepoint. We related a urine marker of oxidative DNA damage to serum isoniazid pharmacokinetic exposures and pharmacogenetics in a clinical study. Results: Among isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-hour dosing interval, hydrazine demonstrated the highest levels of redox imbalance, mitochondrial injury, and oxidative DNA damage over a 28-day treatment period. In a clinical validation study of isoniazid-treated TB patients, peak isoniazid serum concentrations were positively associated with a urine biomarker of oxidative DNA damage. Conclusions: Isoniazid and its metabolites share the potential for oxidative cellular damage, with the greatest effects observed for hydrazine. Future studies should investigate the clinical consequences of oxidative stress with regards to clinical episodes of drug induced liver injury during isoniazid treatment.

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Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity

Cited by 58 publications

References 72 publications

Home-based Anti-Tuberculosis Treatment Adverse Reactions (HATTAR) study: a protocol for a prospective observational study

Home-based Anti-Tuberculosis Treatment Adverse Reactions (HATTAR) study: a protocol for a prospective observational study

Possible association of HMOX1 and NQO1 polymorphisms with anti-tuberculosis drug-induced liver injury: A matched case-control study

Redox imbalance and oxidative DNA damage during isoniazid treatment: A clinical and translational pharmacokinetic study

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