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Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406860/ https://www.ncbi.nlm.nih.gov/pubmed/32848735 http://dx.doi.org/10.3389/fphar.2020.01103 |
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author | Zentner, Isaac Back, Hyun-moon Kagan, Leonid Subbian, Selvakumar Nagajyothi, Jyothi Srivastava, Shashikant Pasipanodya, Jotam Gumbo, Tawanda Bisson, Gregory P. Vinnard, Christopher |
author_facet | Zentner, Isaac Back, Hyun-moon Kagan, Leonid Subbian, Selvakumar Nagajyothi, Jyothi Srivastava, Shashikant Pasipanodya, Jotam Gumbo, Tawanda Bisson, Gregory P. Vinnard, Christopher |
author_sort | Zentner, Isaac |
collection | PubMed |
description | 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-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. 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-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. 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. |
format | Online Article Text |
id | pubmed-7406860 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74068602020-08-25 Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study Zentner, Isaac Back, Hyun-moon Kagan, Leonid Subbian, Selvakumar Nagajyothi, Jyothi Srivastava, Shashikant Pasipanodya, Jotam Gumbo, Tawanda Bisson, Gregory P. Vinnard, Christopher Front Pharmacol Pharmacology 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-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. 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-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. 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. Frontiers Media S.A. 2020-07-29 /pmc/articles/PMC7406860/ /pubmed/32848735 http://dx.doi.org/10.3389/fphar.2020.01103 Text en Copyright © 2020 Zentner, Back, Kagan, Subbian, Nagajyothi, Srivastava, Pasipanodya, Gumbo, Bisson and Vinnard http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Zentner, Isaac Back, Hyun-moon Kagan, Leonid Subbian, Selvakumar Nagajyothi, Jyothi Srivastava, Shashikant Pasipanodya, Jotam Gumbo, Tawanda Bisson, Gregory P. Vinnard, Christopher Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study |
title | Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study |
title_full | Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study |
title_fullStr | Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study |
title_full_unstemmed | Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study |
title_short | Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study |
title_sort | redox imbalance and oxidative dna damage during isoniazid treatment of hiv-associated tuberculosis: a clinical and translational pharmacokinetic study |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406860/ https://www.ncbi.nlm.nih.gov/pubmed/32848735 http://dx.doi.org/10.3389/fphar.2020.01103 |
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