Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen‑induced toxicity in isolated rat hepatocytes

  • Sara Nafisi Biotechnology Research Center, Drug Applied Research Center, Pharmacology and Toxicology Department, School of Pharmacy, Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz
  • Reza Heidari Pharmaceutical Sciences Research Center (PSRC), Shiraz University of Medical Sciences, Shiraz
  • Mohammad Ghaffarzadeh Chemistry and Chemical Engineering Research Center of Iran, Tehran
  • Mojtaba Ziaee Biotechnology Research Center, Drug Applied Research Center
  • Hossein Hamzeiy Biotechnology Research Center, Pharmacology and Toxicology Department, School of Pharmacy
  • Alireza Garjani Drug Applied Research Center, Pharmacology and Toxicology Department, School of Pharmacy
  • Mohammad Ali Eghbal Drug Applied Research Center, Pharmacology and Toxicology Department, School of Pharmacy
Keywords: drug-induced liver injury (DILI), fibrates, mitochondria, oxidative stress, reactive oxygen species (ROS)

Abstract

Acetaminophen (N-acetyl para amino phenol, APAP) is a widely used antipyretic and analgesic drug responsible for various drug-induced liver injuries. This study evaluated APAP-induced toxicity in isolated rat hepatocytes alongside the protective effects of silafibrate and N-acetyl cysteine (NAC). Hepatocytes were isolated from male Sprague-Dawley rats by collagenase enzyme perfusion via the portal vein. This technique is based on liver perfusion with collagenase after removing calcium ions (Ca2+) with a chelator. Cells were treated with different concentrations of APAP, silafibrate, and NAC. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial depolarisation were measured as toxicity markers. ROS formation and lipid peroxidation occurred after APAP administration to rat hepatocytes. APAP caused mitochondrial depolarisation in isolated cells. Administration of silafibrate (200 µmol L-1) and/or NAC (200 µmol L-1) reduced the ROS formation, lipid peroxidation, and mitochondrial depolarisation caused by APAP. Cytotoxicity induced by APAP in rat hepatocytes was mediated by oxidative stress. In addition, APAP seemed to target cellular mitochondria during hepatocyte damage. The protective properties of silafibrate and/or NAC against APAP‑induced hepatic injury may have involved the induction of antioxidant enzymes, protection against oxidative stress and inflammatory responses, and alteration in cellular glutathione content.

How to Cite
1.
Nafisi S, Heidari R, Ghaffarzadeh M, Ziaee M, Hamzeiy H, Garjani A, Eghbal MA. Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen‑induced toxicity in isolated rat hepatocytes. Arh Hig Rada Toksikol [Internet]. 1 [cited 2024Mar.29];65(2). Available from: https://arhiv.imi.hr/index.php/arhiv/article/view/178
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Original article