<i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway
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 cy...
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MDPI AG
2019-02-01
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| Series: | International Journal of Molecular Sciences |
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| author | Mohamed A. Dkhil Ahmed E. Abdel Moneim Taghreed A. Hafez Murad A. Mubaraki Walid F. Mohamed Felwa A. Thagfan Saleh Al-Quraishy |
| author_facet | Mohamed A. Dkhil Ahmed E. Abdel Moneim Taghreed A. Hafez Murad A. Mubaraki Walid F. Mohamed Felwa A. Thagfan Saleh Al-Quraishy |
| author_sort | Mohamed A. Dkhil |
| collection | DOAJ |
| description | 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 <i>Myristica fragrans</i> (nutmeg), kernel extract (MFKE) in respect to paracetamol (acetaminophen; <i>N</i>-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. |
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| spelling | doaj.art-62d18a198ed646619e2d9991b3d4cfb32022-12-22T02:39:47ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-02-0120499310.3390/ijms20040993ijms20040993<i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 PathwayMohamed A. Dkhil0Ahmed E. Abdel Moneim1Taghreed A. Hafez2Murad A. Mubaraki3Walid F. Mohamed4Felwa A. Thagfan5Saleh Al-Quraishy6Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Zoology and Entomology, Faculty of Science, Helwan University, Cairo 11795, EgyptClinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi ArabiaClinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi ArabiaDepartment of Biological and Geological Sciences, Faculty of Education, Ain Shams University, Cairo 11341, EgyptDepartment of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi ArabiaDepartment of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaParacetamol 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 <i>Myristica fragrans</i> (nutmeg), kernel extract (MFKE) in respect to paracetamol (acetaminophen; <i>N</i>-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.https://www.mdpi.com/1422-0067/20/4/993paracetamol<i>Myristica fragrans</i> kernelsheme oxygenase 1liver |
| spellingShingle | Mohamed A. Dkhil Ahmed E. Abdel Moneim Taghreed A. Hafez Murad A. Mubaraki Walid F. Mohamed Felwa A. Thagfan Saleh Al-Quraishy <i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway International Journal of Molecular Sciences paracetamol <i>Myristica fragrans</i> kernels heme oxygenase 1 liver |
| title | <i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway |
| title_full | <i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway |
| title_fullStr | <i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway |
| title_full_unstemmed | <i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway |
| title_short | <i>Myristica fragrans</i> Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway |
| title_sort | i myristica fragrans i kernels prevent paracetamol induced hepatotoxicity by inducing anti apoptotic genes and nrf2 ho 1 pathway |
| topic | paracetamol <i>Myristica fragrans</i> kernels heme oxygenase 1 liver |
| url | https://www.mdpi.com/1422-0067/20/4/993 |
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