Background and Aim: Fipronil (FPN) is a potent pesticide that is heavily used around the world in agriculture. However, its irrational use could potentially have deleterious effects on animals and humans. The present study aimed to investigate the ability of sitagliptin (Sit) and losartan (LOS), when used both individually or concurrently, to guard rat liver against the acute hepatotoxicity caused by FPN.

Materials and Methods: Forty-two adult male Wistar rats were equally divided into seven groups (6/group). Group I (control) received normal saline (0.5 mL/rat, vehicle for all treatments) by gavage once daily for 10 days. Group II received oral Sit (10 mg/kg body weight [BW]) daily for 10 days and Group III received oral LOS (5 mg/kg BW) daily for 10 days. Group IV received oral FPN (19.4 mg/kg BW; 1/5 of the oral LD₅₀) for the past 5 days of the study. Groups V and VI received oral Sit (10 mg/kg BW) and LOS (5 mg/kg BW) daily, respectively, 5 days prior and 5 days during FPN administration (19.4 mg/kg BW). Group VII received oral Sit (10 mg/kg BW) and LOS (5 mg/kg BW) for 10 days with daily FPN during the past 5 days. After the end of the treatment period, the rats were humanely sacrificed and blood and liver tissue samples were collected for biochemical analysis and histopathological and immunohistochemical investigations.

Results: FPN administration resulted in elevated alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase serum concentrations as well as increased malondialdehyde levels and reduced catalase, superoxide dismutase, glutathione peroxidase, and glutathione activity. The histopathological investigation showed disorganization of the hepatic cords and focal necrosis of the hepatocytes in FPN-intoxicated rats. Furthermore, the immunohistochemical examination showed that hepatic caspase-3 was overexpressed in the FPN-treated rats. The administration of Sit and LOS before and alongside FPN markedly mitigated the alterations caused by FPN and the hepatoprotective effects were more prominent in the combination group.

Conclusion: Sit and LOS, both individually or in combination, confers considerable hepatoprotection against FPN-induced hepatotoxicity.

Keywords: fipronil, hepatotoxicity, losartan, oxidative stress, sitagliptin.