Favipiravir induces oxidative stress and genotoxicity in cardiac and skin cells

Gunaydin-Akyildiz A., Aksoy N., Boran T., Ilhan E. N., ÖZHAN G.

TOXICOLOGY LETTERS, cilt.371, ss.9-16, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 371
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1016/j.toxlet.2022.09.011
  • Dergi Adı: TOXICOLOGY LETTERS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aerospace Database, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Chimica, Communication Abstracts, EMBASE, Environment Index, Food Science & Technology Abstracts, MEDLINE, Metadex, Veterinary Science Database, Civil Engineering Abstracts
  • Sayfa Sayıları: ss.9-16
  • Anahtar Kelimeler: Favipiravir, Oxidative stress, DNA damage, Genotoxicity, Cardiotoxicity, Dermal toxicity, Mitochondrial toxicity, ACCURATE DOCKING, IN-VITRO, TOXICITY, DRUGS, PROTEIN, GLIDE, T-705
  • İstanbul Üniversitesi Adresli: Evet

Özet

Favipiravir (T-705), used against influenza viruses, is approved for emergency use in many countries for the treatment of COVID-19. The frequent adverse effects of favipiravir are related with the gastrointestinal system, however, studies suggest a positive association of favipiravir on QTc prolongation, which can cause cardiotox-icity. Also, there are reports of skin reactions such as angioedema due to favipiravir. Despite the several adverse effects, studies examining the drug's effects at the molecular level are insufficient, e.g., the genotoxic and oxidative stress-inducing effects of favipiravir, which are among the primary mechanisms of drug-induced toxicity. The cytotoxicity of favipiravir was analyzed with the measurement of the ATP content in H9c2 car-diomyoblasts and CCD-1079Sk skin fibroblasts. The ATP level decreased starting from 200 mu M. The inhibitory effect on the mitochondrial electron transport chain enzymes complex I and complex V was also evaluated where favipiravir showed significant enzyme inhibitory effects in the highest concentration studied. A molecular docking study evaluating the interaction between favipiravir-RTP and mitochondrial DNA polymerase (POLG1) was done. The relationship of favipiravir with oxidative stress was examined by measuring glutathione (GSH) and protein carbonyl levels which were observed higher after drug treatment compared to the control group. The genotoxicity study was done using the Comet assay and increase in DNA tail has been detected. Furthermore, 8-OHdG levels were measured higher in favipiravir treated cells indicating oxidative DNA damage. Favipiravir induced oxidative stress leading to DNA damage in cardiomyoblast cells and fibroblastic skin cells. Oxidative stress and DNA damage might eventually lead to organ-specific damage such as cardiotoxicity and dermal toxicity. Considering the increased use of favipiravir in recent years, and that oxidative stress and genotoxicity are two important indicators of drug-induced toxicity, the obtained results are worth attention.