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Isoniazid-induced apoptosis in HepG2 cells: generation of oxidative stress and Bcl-2 down-regulation
Smrati Bhadauria1, Rajeev Mishra, Ranjana Kanchan
1Division of Toxicology, Central Drug Research Institute, Lucknow 262 001, (CSIR) India. smraticdri@gmail.com
Abstract:
Isoniazid (INH) is a first-line antibiotic used in the treatment of infections caused by Mycobacterium tuberculosis. However it has a serious limitation of being hepatotoxic. Delineating the mechanism underlying INH-induced hepatotoxicity may be beneficial in devising ways to counteract its toxic manifestations. Studies in human hepatoma HepG2 cells have indicated that INH exposure causes induction of apoptosis. This study was aimed at identifying the key components/pathways of the INH-induced apoptotic pathway using HepG2 cells. HepG2 cells were exposed to increasing concentrations of INH (6.5, 13, 26, and 52 mM). Hydrogen peroxide (0.3 mM) served as positive control. After incubating for specific time intervals cells were harvested and evidences of cytotoxicity, oxidative stress, and apoptosis were sought. The findings indicated that INH exposure causes increased ROS generation along with alteration in levels of enzymatic antioxidants such as Superoxide dismutase, Catalase, and Glucose-6-Phosphate dehydrogenase. Altered Bcl-2/Bax content, cytochrome-c translocation, caspase activation, and DNA fragmentation emphasized involvement of apoptosis.
Insights
Isoniazid (INH) antibiotic causes liver damage by inducing apoptosis in HepG2 cells. This involves oxidative stress, altered antioxidant enzymes, and key apoptotic pathway components, offering insights into mitigating INH hepatotoxicity.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Isoniazid (INH) is a crucial first-line drug for tuberculosis treatment.
- INH exhibits significant hepatotoxicity, a major clinical limitation.
- Understanding INH-induced liver injury mechanisms is vital for therapeutic strategies.
Purpose of the Study:
- To elucidate the specific molecular pathways and key components involved in Isoniazid-induced apoptosis.
- To investigate the role of oxidative stress in Isoniazid's cytotoxic effects.
- To utilize human hepatoma HepG2 cells as a model system for studying INH toxicity.
Main Methods:
- HepG2 cells were treated with varying concentrations of Isoniazid (6.5–52 mM).
- Assays were performed to detect cytotoxicity, reactive oxygen species (ROS) generation, and antioxidant enzyme activity.
- Apoptosis markers including Bcl-2/Bax ratio, cytochrome-c release, caspase activation, and DNA fragmentation were analyzed.
Main Results:
- Isoniazid exposure led to increased ROS production in HepG2 cells.
- Alterations in Superoxide Dismutase, Catalase, and Glucose-6-Phosphate Dehydrogenase levels were observed.
- Evidence of apoptosis induction was confirmed through changes in Bcl-2/Bax expression, cytochrome-c translocation, caspase activation, and DNA fragmentation.
Conclusions:
- Isoniazid induces apoptosis in HepG2 cells, mediated by oxidative stress and dysregulation of antioxidant enzymes.
- The intrinsic apoptotic pathway, involving Bcl-2 family proteins, mitochondria, and caspases, is activated by INH.
- These findings provide a mechanistic basis for INH-induced hepatotoxicity and suggest potential targets for intervention.
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