Phenelzine protects against acetaminophen induced apoptosis in HepG2 cells

TÜYLÜ KÜÇÜKKILINÇ Z. T., ERCAN A.

Drug and Chemical Toxicology, cilt.47, sa.1, ss.81-89, 2024 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 47 Sayı: 1
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1080/01480545.2023.2217696
  • Dergi Adı: Drug and Chemical Toxicology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, Environment Index, Food Science & Technology Abstracts, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.81-89
  • Anahtar Kelimeler: Acetaminophen, phenelzine, drug repurposing, reactive oxygen species, PERK, CYP 450 enzymes
  • Hacettepe Üniversitesi Adresli: Evet

Özet

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.