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.