ArticleFrontiers in pharmacology2020
Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study.
Article in Frontiers in pharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
4 citing papers in PubMed, 8 citations in OpenAlex.
- Isoniazid subverting erythrocyte homeostasis: implications for tuberculosis therapy.Frontiers in pharmacology · 2026Article
- Inclusion of patient-centered, non-microbiological endpoints and biomarkers in tuberculosis drug trials.Frontiers in antibiotics · 2025Review
- Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement.Frontiers in pharmacology · 2024Review
- Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study.Frontiers in pharmacology · 2020Article
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe 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.
methodsWe 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-h 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.
resultsAmong isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-h 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.
conclusionsIsoniazid 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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