Phenelzine protects against acetaminophen induced apoptosis in HepG2 cells

Abstract

Acetaminophen (APAP) overdosing is the most common cause of drug-induced liver failure. Despite extensive study, N-acetylcysteine is currently the only antidote utilized for treatment. The purpose of this study was to evaluate the effect and mechanisms of phenelzine, an FDA-approved antidepressant, on APAP-induced toxicity in HepG2 cells. The human liver hepatocellular cell line HepG2 was used to investigate APAP-induced cytotoxicity. The protective effects of phenelzine were determined by examining the cell viability, combination index calculation, Caspase 3/7 activation, Cytochrome c release, H₂O₂ levels, NO levels, GSH activity, PERK protein levels, and pathway enrichment analysis. Elevated H₂O₂ production and decreased glutathione (GSH) levels were indicators of APAP-induced oxidative stress. The combination index of 2.04 indicated that phenelzine had an antagonistic effect on APAP-induced toxicity. When compared to APAP alone, phenelzine treatment considerably reduced caspase 3/7 activation, cytochrome c release, and H₂O₂ generation. However, phenelzine had minimal effect on NO and GSH levels and did not alleviate ER stress. Pathway enrichment analysis revealed a potential connection between APAP toxicity and phenelzine metabolism. These findings suggested that phenelzine’s protective effect against APAP-induced cytotoxicity could be attributed to the drug’s capacity to reduce APAP-mediated apoptotic signaling.

Keywords:

• Acetaminophen
• phenelzine
• drug repurposing
• reactive oxygen species
• PERK
• CYP 450 enzymes

Author contributions

Ayşe Ercan conducted most of the experiments and analyzed the data. Tuba Tüylü Küçükkılınç designed the experiments, improved the analysis through constructive debate, and wrote the manuscript. All authors read and approved the final manuscript.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability statement

The data that support the findings of this study are available from the corresponding author, T.T.K., upon reasonable request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.