Abstract
Paracetamol is responsible for acute liver failure in humans and experimental animals when taken at high doses and transformed into a reactive metabolite by the liver cytochrome P450. On the other hand, nutmeg is rich with many phytochemical ingredients that are known for their ability to inhibit cytochrome P450. Hence, the present experiment was aimed at studying the hepatoprotective effect of Myristica fragrans (nutmeg), kernel extract (MFKE) in respect to paracetamol (acetaminophen; N-acetyl-p-amino-phenol (APAP))-induced hepatotoxicity in rats, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic activities. Liver toxicity was induced in rats by a single oral administration of APAP (2 g/kg). To evaluate the hepatoprotective effect of MFKE against this APAP-induced hepatotoxicity, rats were pre-treated with either oral administration of MFKE at 300 mg/kg daily for seven days or silymarin at 50 mg/kg as a standard hepatoprotective agent. APAP intoxication caused a drastic elevation in liver function markers (transaminases, alkaline phosphatase, and total bilirubin), oxidative stress indicators (lipid peroxidation and nitric oxide), inflammatory biomarkers (tumour necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and nuclear factor ĸB) and the pro-apoptotic BCL2 Associated X (Bax) and caspases-3 genes. Furthermore, analyses of rat liver tissue revealed that APAP significantly depleted glutathione and inhibited the activities of antioxidant enzymes in addition to downregulating two key anti-apoptotic genes: Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) and B-cell lymphoma 2 (Bcl-2). Pre-treatment with MFKE, however, attenuated APAP-induced liver toxicity by reversing all of these toxicity biomarkers. This hepatoprotective effect of MFKE was further confirmed by improvement in histopathological findings. Interestingly, the hepatoprotective effect of MFKE was comparable to that offered by the reference hepatoprotector, silymarin. In conclusion, our results revealed that MFKE had antioxidant, anti-inflammatory, and anti-apoptotic properties, and it is suggested that this hepatoprotective effect could be linked to its ability to promote the nuclear factor erythroid 2–related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway.
Highlights
The liver is one of the most important organs in the body, performing up to 500 functions
The High performance liquid chromatography (HPLC) profile of MFKE shows the presence of 25 peaks with retention times ranging from 2.768 min to 40.842 min
There was no prevalence of mortality and APAP administration did not cause any abnormal clinical signs, with no change in food and water consumption in the groups that received APAP
Summary
The liver is one of the most important organs in the body, performing up to 500 functions. At toxic doses, APAP quickly depletes GSH, resulting in the accumulation of NAPQI, which forms NAPQI-protein adducts as a result of covalent bond formation between NAPQI and –SH group of hepatocyte proteins [5]. The accumulation of these NAPQI-protein adducts results in turn in the formation of reactive oxygen species (ROS) that attack the cellular micro molecules causing lipid peroxidation and hepatic necrosis [6]. We explored the protective role of M. fragrans kernel extract against hepatotoxicity induced by APAP. The effect of M. fragrans kernel extract was compared with that of silymarin, a standard hepatoprotective agent
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