Abstract
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-α 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 cells' 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.
Highlights
The liver is the largest internal organ in the human body, and it is the chief site for intense anabolism, catabolism, and excretion [1, 2]
It was reported that APAP could induce organ damage by activating apoptotic death and inflammation which were manifested by an increase in the expression of caspase-3, caspase-9, protein 53 (p53), nuclear factor-kappa B (NF-κB), and inducible nitric oxide synthase as well as by a decrease in B-cell lymphoma-2 (Bcl-2) expression [15, 16]
5-Hydroxymethylfurfural, 4-hexen-3-one, 4,5-dimethyl, dodecane, and lupanine have the highest percent of total
Summary
The liver is the largest internal organ in the human body, and it is the chief site for intense anabolism, catabolism, and excretion [1, 2] It plays a major role in detoxification and excretion of many exogenous and endogenous compounds; any impairment of its structural integrity and functions may cause many implications on one’s health [3]. Reactive oxygen species (ROS) production was found to be associated with excessive and long-term APAP administration and biotransformation [13] In this regard, many investigators stated that oxidative stress plays a pivotal role in the pathogenesis of drug-induced damage and has been implicated in the mechanisms of action that lead to necrosis [14]. It was elucidated by other publication that p53 prevents progression of liver injury by maintaining mitochondrial and metabolic homeostasis after APAP overdose-induced acute liver injury [17]
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