The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.
Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS.
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Saliha Sena
SS
Karcioglu
Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey.
Saziye Sezin
SS
Palabiyik
Department of Biochemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey.
Yasin
Y
Bayir
Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey.
Emre
E
Karakus
Department of Histology and Embryology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey.
Tolga
T
Mercantepe
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Zekai
Z
Halici
Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey.
Abdulmecit
A
Albayrak
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000577:Amides / Q000494:pharmacology* / Q000627:therapeutic use; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy*; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016877:Oxidants / Q000378:metabolism; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000092502:Renin Inhibitors
D000082:Acetaminophen; D000410:Alanine Transaminase; D000577:Amides; D000804:Angiotensin II; D000975:Antioxidants; D001219:Aspartate Aminotransferases; D005650:Fumarates; D016877:Oxidants; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren
ALISKIREN; HEPATOTOXICITY; PARACETAMOL; RAT; TGF-β