Effects of N-acetyl cysteine and cyclosporin A on acetaminophen-induced acute liver injury in mice

Acetaminophen (APAP)- induced N-acetyl-para-benzoquinone imine (NAPQI), which increases due to glutathione (GSH) depletion in acute liver injury, covalently binds to cellular proteins causing apoptotic and / or necrotic cell death. In the study, we aimed to investigate the effects of glutathione precursor N-acetyl cysteine (NAC) and inhibitor of mitochondrial permeability pore transport cyclosporine A (CsA) on liver tissue damage in mice treated with high dose acetaminophen. A total of 78 adult Balb-c male mice were collected under 13 groups (n = 6). NAC (1200 mg/kg), CsA (50 mg/kg) and APAP (400 mg/kg) groups were administered simultaneously at the beginning of the experiment. In the treatment groups, NAC (1200 mg / kg), CsA (50 mg / kg) or NAC (1200 mg / kg) + CsA (50 mg / 1 hour) were applied after 1 hour, 3 hours or 5 hours after APAP (400 mg / kg) injection by intraperitoneal injection. The experiment was terminated 12 hours after APAP injections. Hematoxylin-eosin staining and transmission electron microscopy were used for tissue damage detection and TUNEL method was used for the evaluation of apoptotic cells. qRT-PCR for the determination of cytochrome c gene expression, immunohistochemical staining for the detection of cytochrome c and 3-nitrotyrosine at the protein level, biochemical analyzes for the determination of AST-ALT and liver GSH levels were performed. After 12 hours of high-dose APAP injection, hepatotoxicity findings such as various histopathological and ultrastructural changes like centrilobular necrosis, sinusoidal dilatation, vascular congestion, mitochondrial damage, elevated AST-ALT levels, and decreased GSH levels were detected. It was revealed that the most successful treatments given after 1 hour of APAP treatment was NAC alone, and the most successful treatment after 3 and 5 hours was obtained with the combination of both drugs. In conclusion, in case of acute liver injury caused by APAP which cannot be noticed in the early period, it was concluded that CsA administration in addition to routine NAC treatment may be effective in reducing this damage.