Isoniazid subverting erythrocyte homeostasis: implications for tuberculosis therapy

Area of Science:

• Biochemistry
• Molecular Biology
• Hematology

Background:

• Isoniazid (INH) is a primary anti-tuberculosis drug.
• Understanding INH's impact on antioxidant defense in erythrocytes is crucial for therapy safety.
• Erythrocytes are particularly susceptible to oxidative damage.

Purpose of the Study:

• To investigate the molecular mechanisms of INH-induced oxidative stress in human blood cells.
• To identify key genes and pathways affected by INH treatment.
• To validate transcriptomic findings with biochemical assays in erythrocytes.

Main Methods:

• Transcriptomic analysis of INH-treated HepG2 cells to identify differentially expressed genes (DEGs).
• Cross-referencing DEGs with oxidative stress gene sets and constructing protein-protein interaction networks.
• In vitro biochemical assays to assess antioxidant enzyme activities, erythrocyte morphology, membrane integrity, and calcium involvement.

Main Results:

• Identified 7202 DEGs, with 196 overlapping oxidative stress genes.
• Key antioxidant genes (SOD1, SOD2, GPx) were downregulated, correlating with reduced enzyme activity.
• INH induced erythrocyte membrane blebbing and volume expansion, mediated by calcium influx, leading to increased fragility.

Conclusions:

• INH disrupts erythrocyte redox balance by suppressing antioxidant enzymes and activating oxidative stress pathways.
• Calcium influx plays a critical role in INH-induced erythrocyte membrane destabilization.
• Monitoring for oxidative damage is essential for patients undergoing INH therapy.