The Preventive Effects and the Mechanisms of Action of Navel Orange Peel Hydroethanolic Extract, Naringin, and Naringenin in N-Acetyl-p-aminophenol-Induced Liver Injury in Wistar Rats

N-Acetyl-p-aminophenol (APAP) or acetaminophen is the most common drug ingredient worldwide. It is found in more than 600 different over-the-counter and prescription medicines. Its long-term and overdose use is highly toxic and may result in liver injury. Thus, this study was designed to assess the preventive effects and to suggest the mechanisms of action of the navel orange peel hydroethanolic extract, naringin, and naringenin in APAP-induced hepatotoxicity in male Wistar rats. APAP was administered to male Wistar rats at a dose level of 0.5 g/kg body weight (b.w.) by oral gavage every other day for 4 weeks. APAP-administered rats were treated with the navel orange peel hydroethanolic extract (50 mg/kg b.w.), naringin (20 mg/kg b.w.), and naringenin (20 mg/kg b.w.) by oral gavage every other day during the same period of APAP administration. The treatments of APAP-administered rats with the peel extract, naringin, and naringenin produced a significant decrease in the elevated serum AST, ALT, ALP, LDH, and GGT activities as well as total bilirubin and TNF-alpha levels while they induced a significant increase in the lowered serum albumin and IL-4 levels. The treatments also resulted in a significant decrease in the elevated liver lipid peroxidation and enhanced the liver GSH content and SOD, GST, and GPx activities as compared with APAP-administered control; the peel extract was the most potent in improving the liver LPO, GSH content, and GPx activity. In addition, the three treatments significantly downregulated the elevated hepatic proapoptotic mediators p53, Bax, and caspase-3 and significantly upregulated the suppressed antiapoptotic protein, Bcl-2, in APAP-administered rats. In association, the treatments markedly amended the APAP-induced liver histopathological deteriorations that include hepatocyte steatosis, cytoplasmic vacuolization, hydropic degeneration, and necrosis together with mononuclear leucocytic and fibroblastic inflammatory cell's infiltration. In conclusion, the navel orange peel hydroethanolic extract, naringin, and naringenin may exert their hepatopreventive effects in APAP-administered rats via enhancement of the antioxidant defense system and suppression of inflammation and apoptosis.