Effect of Ethanol Leaf Extract of Annona senegalensis on Lipid Profile and Kidney Function in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Rats
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374-398
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Sep 9, 2025
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10.58578/ajbmbr.v2i3.7363
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Authors:Isaac John Umaru1, Usman Lukman Adamu2, Mosugu Ovayoza Omolara3, Ogar Fonne Okang4, Ingwu Joseph Akem5, Akafa Andes Tansaba6, Shadrach Philip7, Otashu Kenneth Frank8
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Abstract
Liver cancer remains a major global health burden, with hepatocellular carcinoma (HCC) being the most common form and a leading cause of cancer-related deaths. Its progression is often accompanied by metabolic and renal dysfunction, complicating treatment outcomes. While conventional therapies such as chemotherapy, radiotherapy, and targeted drug treatments offer benefits, they are frequently associated with high toxicity and adverse side effects. This discussion highlights the potential of Annona senegalensis as a safer alternative for managing HCC-related complications, particularly in the context of lipid metabolism and renal function. Evidence from experimental studies suggests that the ethanolic leaf extract of A. senegalensis significantly improves lipid profiles by reducing cholesterol levels from 368.57 ± 1.72 in the negative control group to 266.40 ± 0.88, 217.46 ± 0.82, and 182.24 ± 1.20 at 200, 400, and 600 mg/kg doses, respectively, while maintaining favorable HDL levels at higher doses. These findings indicate the extract’s potential to enhance lipid metabolism, lower cardiovascular risk, and provide renal protection during liver cancer progression. Beyond its biochemical effects, the study reinforces the growing relevance of integrating traditional medicinal plants into modern healthcare frameworks as complementary therapeutic options. Overall, A. senegalensis demonstrates promising hepatoprotective, metabolic, and nephroprotective effects, warranting further investigation into its bioactive compounds and clinical applicability.
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Ethanol; Leaves; Annona senegalensis; Lipid Profile; Kidney Function; Diethylnitrosamine; Hepatocellular Carcinoma; Wistar Rats
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Umaru, I. J., Adamu, U. L., Omolara, M. O., Okang, O. F., Akem, I. J., Tansaba, A. A., Philip, S., & Frank, O. K. (2025). Effect of Ethanol Leaf Extract of Annona senegalensis on Lipid Profile and Kidney Function in Diethylnitrosamine-Induced Hepatocellular Carcinoma in Rats. African Journal of Biochemistry and Molecular Biology Research, 2(3), 374-398. https://doi.org/10.58578/ajbmbr.v2i3.7363
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
References
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Ahmed, M.U., R.O. Arise, and I.Y. Sudi. (2020) Evaluation of the Antidiarrhoeal Activity of Aqueous Root and Stem Bark Extracts of Annona senegalensis. International Journal of Life Sciences and Biotechnology. 3(1): p. 1-17. DOI: 10.38001/ijlsb.656112
Andrikoula M, Avades T. Hypolipidaemia is not always indicating liver dysfunction. A review of primary and secondary high-density lipoprotein and low-density lipoprotein deficiencies. Minerva Med. 2006 Dec; 97(6):487-94.
Bai, L., Sun, H., Zhou, C., Xu, Y., Zhang, X., & Huang, Y. (2021). DEN-induced hepatocellular carcinoma in animal models: Mechanisms and therapeutic insights. Frontiers in Oncology, 11, 656769.
Bassendine MF, Sheridan DA, Bridge SH, Felmlee DJ, Neely RD. Lipids and HCV. Semin Immunopathol 2013; 35:87–100.
Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepato-cellular carcinoma
Breier C, Lisch HJ, Braunsteiner H. Lipoproteins, HDLapolopoproteins, activities of hepatic lipase and lecithincholesterol acyltransferase in the plasma of patients with postalcoholic end-stage liver cirrhosis. Klin Wochenschr. 1983 Sep 15; 61(18):929-31.
Cascaes, M. M., Carneiro, O. D. S., Nascimento, L. D. D., de Moraes, Â. A. B., de Oliveira, M. S., Cruz, J. N. and Andrade, E. H. D. A. (2021). Essential oils from Annonaceae species from Brazil: a systematic review of their phytochemistry, and biological activities. International Journal of Molecular Sciences, 22(22), 12140.
Connor, F., Rayner, T. F., Aitken, S. J., Feig, C., Lukk, M., Santoyo-Lopez, J. and Odom, D. T. (2018). Mutational landscape of a chemically-induced mouse model of liver cancer. Journal of hepatology, 69(4), 840-850.
Egydio-Brandão, A. P. M., Novaes, P. and Santos, D. Y. A. C. (2017). Alkaloids from Annona: Review from 2005 to 2016. JSM Biochem Mol Biol, 4(3), 1031.
Emmanuel, N. and Mamoudou, S. (2015). Some Investigations on the Traditional Pharmacopoeia about Venomous Bites and Stings from Scorpions, Snakes and Spiders; in the Hina Subdivision, Far-North, Cameroon. British Journal of Pharmaceutical Research, 5(5), 344-358.
Farber, E. (2019). Chemical carcinogenesis in the liver: Diethylnitrosamine as an experimental model. Cancer Research, 39(9), 3152-3160.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 01;136(5):E359-86. [PubMed]
Ghadir MR, Riahin AA, Havaspour A, Nooranipour M, Habibinejad AA. The relationship between lipid profile and severity of liver damage in cirrhotic patients. Hepat Mon 2010; 10:285–288.
Halliwell, B., & Gutteridge, J. M. (2015). Free Radicals in Biology and Medicine (5th ed.). Oxford University Press.
He, J., Sun, X., Yang, X., Wu, Y., Wang, H., & Liu, H. (2015). The involvement of Wnt/β-catenin signaling pathway in DEN-induced hepatocarcinogenesis in mice. International Journal of Molecular Medicine, 35(5), 1403-1410.
Hou, X. J., Ye, F., Li, X. Y., Liu, W. T., Jing, Y. Y., Han, Z. P. and Wei, L. X. (2018). Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cellular immunology, 326, 52-59.
Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007 Aug;5(8):938-45, 945.e1-4. [PubMed]
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Jada, M. S., Usman, W. A. and Olabisi, A. O. (2014). Crude flavonoids isolated from the stem bark of Annona senegalese have antimicrobial activity. Journal of Advances in Biology & Biotechnology, 2(1), 24-29.
Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, Mariotto A, Lake AJ, Wilson R, Sherman RL, Anderson RN, Henley SJ, Kohler BA, Penberthy L, Feuer EJ, Weir HK. Annual Report to the Nation on the Status of Cancer, 1975-2014, Featuring Survival. J Natl Cancer Inst. 2017 Sep 01;109(9) [PMC free article] [PubMed]
Jiang M, Liu F, Xiong WJ, Zhong L, Xu W, Xu F, et al. Combined MELD and blood lipid level in evaluating the prognosis of decompensated cirrhosis. World J Gastroenterol 2010; 16:1397–1401.
Luch, A. (2005). The carcinogenic effects of environmental factors. Mutation Research/Reviews in Mutation Research, 589(1), 23–35. [DOI: 10.1016/j.mrrev.2005.03.002].
Mansour, D. F., Abdallah, H. M., Ibrahim, B. M., Hegazy, R. R., Esmail, R. S. and Abdel-Salam, L. O. (2019). The carcinogenic agent diethylnitrosamine induces early oxidative stress, inflammation and proliferation in rat liver, stomach and colon: protective effect of ginger extract. Asian Pacific journal of cancer prevention: APJCP, 20(8), 2551
Musa, D. D., Anakaa, T. M. and Bashir, K. A. (2017). Phytochemical analysis of crude extracts from Annona senegalese (L) and its anti-snake venom potential on albino rats. Fudma journal of Sciences, 1(1), 139-142.
Napolitano M, Giuliani A, Alonzi T, Mancone C, D’Offizi G, Tripodi M, et al. Very low-density lipoprotein and low-density lipoprotein isolated from patients with hepatitis C infection induce altered cellular lipid metabolism. J Med Virol 2007; 79:254– 258.
Nashaat EH. Comparative study of serum lipid profile between chronic hepatitis C Egyptian patients and normal controls and the effect of viral eradication on lipids profile. Report Opinion 2010; 2:14–20.
Okhale, S. E., Akpan, E., Fatokun, O. T., Esievo, K. B. and Kunle, O. F. (2016). Annona senegalese Persoon (Annonaceae): A review of its ethnomedicinal uses, biological activities and phytocompounds. Journal of Pharmacognosy and Phytochemistry, 5(2), 211-219.
Okhale, S. E., Akpan, E., Fatokun, O. T., Esievo, K. B. and Kunle, O. F. (2016). Annona senegalese Persoon (Annonaceae): A review of its ethnomedicinal uses, biological activities and phytocompounds. Journal of Pharmacognosy and Phytochemistry, 5(2), 211-219.
Pogribny, I. P., & Rusyn, I. (2013). Role of epigenetic alterations in DEN-induced liver carcinogenesis. Toxicological Sciences, 135(2), 291-299.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646– 649.
Romeiras, M. M., Duarte, M. C., Francisco-Ortega, J., Catarino, L. and Havik, P. (2018). Recovering plant data for guinea-bissau: implications for biodiversity knowledge of West Africa. Diversity, 10(4), 109.
Sayiner, M., Golabi, P. and Younossi, Z. M. (2019). Disease burden of hepatocellular carcinoma: a global perspective. Digestive diseases and sciences, 64, 910-917.
Selimoglu MA, Aydogdu S, Yagci RV. Lipid parameters in childhood cirrhosis and chronic liver disease. Pediatr Int 2002. 44(4): 400-403
Sies, H., & Jones, D. P. (2007). Oxidative Stress and Antioxidant Defense: The Redox Code. Antioxidants & Redox Signaling, 9(7), 2071–2083. [DOI: 10.1089/ars.2007.1766]
Studenik P. Lipid disorders in liver diseases. VnitrLek 2000; 46:547–548.
Tolba, R., Kraus, T., Liedtke, C., Schwarz, M. and Weiskirchen, R. (2015). Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. Laboratory animals, 49(1), 59-69.
Tsai MH, Peng YS, Chen YC, Lien JM, Tian YC, Fang JT, et al. Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. J Hepatol 2009; 50:906–915.
Unsal, V. and Belge-Kurutaş, E. (2017). Experimental hepatic carcinogenesis: oxidative stress and natural antioxidants. Open Access Macedonian Journal of Medical Sciences, 5(5), 686.
Xu, X., Lei, Y., Chen, L., Zhou, H., Liu, H., Jiang, J. and Wu, B. (2021). Phosphorylation of NF-κBp65 drives inflammation-mediated hepatocellular carcinogenesis and is a novel therapeutic target. Journal of Experimental & Clinical Cancer Research, 40(1), 253.
You, Y., Zhu, F., Li, Z., Zhang, L., Xie, Y., Chinnathambi, A. and Lu, B. (2021). Phyllanthin prevents diethylnitrosamine (DEN) induced liver carcinogenesis in rats and induces apoptotic cell death in HepG2 cells. Biomedicine & Pharmacotherapy, 137, 111335.
Zhang, J., Shen, W., & Li, Y. (2019). High-fat diet exacerbates DEN-induced hepatocellular carcinoma. Hepatology, 70(5), 1623-1635.
AgroForestry Tree Database (2013). Annona senegalese. Archived from the original on April 16, 2013. Retrieved August 3, 2010
Ahmed, M.U., R.O. Arise, and I.Y. Sudi. (2020) Evaluation of the Antidiarrhoeal Activity of Aqueous Root and Stem Bark Extracts of Annona senegalensis. International Journal of Life Sciences and Biotechnology. 3(1): p. 1-17. DOI: 10.38001/ijlsb.656112
Andrikoula M, Avades T. Hypolipidaemia is not always indicating liver dysfunction. A review of primary and secondary high-density lipoprotein and low-density lipoprotein deficiencies. Minerva Med. 2006 Dec; 97(6):487-94.
Bai, L., Sun, H., Zhou, C., Xu, Y., Zhang, X., & Huang, Y. (2021). DEN-induced hepatocellular carcinoma in animal models: Mechanisms and therapeutic insights. Frontiers in Oncology, 11, 656769.
Bassendine MF, Sheridan DA, Bridge SH, Felmlee DJ, Neely RD. Lipids and HCV. Semin Immunopathol 2013; 35:87–100.
Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepato-cellular carcinoma
Breier C, Lisch HJ, Braunsteiner H. Lipoproteins, HDLapolopoproteins, activities of hepatic lipase and lecithincholesterol acyltransferase in the plasma of patients with postalcoholic end-stage liver cirrhosis. Klin Wochenschr. 1983 Sep 15; 61(18):929-31.
Cascaes, M. M., Carneiro, O. D. S., Nascimento, L. D. D., de Moraes, Â. A. B., de Oliveira, M. S., Cruz, J. N. and Andrade, E. H. D. A. (2021). Essential oils from Annonaceae species from Brazil: a systematic review of their phytochemistry, and biological activities. International Journal of Molecular Sciences, 22(22), 12140.
Connor, F., Rayner, T. F., Aitken, S. J., Feig, C., Lukk, M., Santoyo-Lopez, J. and Odom, D. T. (2018). Mutational landscape of a chemically-induced mouse model of liver cancer. Journal of hepatology, 69(4), 840-850.
Egydio-Brandão, A. P. M., Novaes, P. and Santos, D. Y. A. C. (2017). Alkaloids from Annona: Review from 2005 to 2016. JSM Biochem Mol Biol, 4(3), 1031.
Emmanuel, N. and Mamoudou, S. (2015). Some Investigations on the Traditional Pharmacopoeia about Venomous Bites and Stings from Scorpions, Snakes and Spiders; in the Hina Subdivision, Far-North, Cameroon. British Journal of Pharmaceutical Research, 5(5), 344-358.
Farber, E. (2019). Chemical carcinogenesis in the liver: Diethylnitrosamine as an experimental model. Cancer Research, 39(9), 3152-3160.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 01;136(5):E359-86. [PubMed]
Ghadir MR, Riahin AA, Havaspour A, Nooranipour M, Habibinejad AA. The relationship between lipid profile and severity of liver damage in cirrhotic patients. Hepat Mon 2010; 10:285–288.
Halliwell, B., & Gutteridge, J. M. (2015). Free Radicals in Biology and Medicine (5th ed.). Oxford University Press.
He, J., Sun, X., Yang, X., Wu, Y., Wang, H., & Liu, H. (2015). The involvement of Wnt/β-catenin signaling pathway in DEN-induced hepatocarcinogenesis in mice. International Journal of Molecular Medicine, 35(5), 1403-1410.
Hou, X. J., Ye, F., Li, X. Y., Liu, W. T., Jing, Y. Y., Han, Z. P. and Wei, L. X. (2018). Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cellular immunology, 326, 52-59.
Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007 Aug;5(8):938-45, 945.e1-4. [PubMed]
Izah, S. C., Ogidi, O. I., Ogwu, M. C., Salimon, S. S., Yusuf, Z. M., Akram, M. and Iyingiala, A. A. (2024). Historical perspectives and overview of the value of herbal medicine. In Herbal Medicine Phytochemistry: Applications and Trends (pp. 3-35). Cham: Springer International Publishing.
Jada, M. S., Usman, W. A. and Olabisi, A. O. (2014). Crude flavonoids isolated from the stem bark of Annona senegalese have antimicrobial activity. Journal of Advances in Biology & Biotechnology, 2(1), 24-29.
Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, Mariotto A, Lake AJ, Wilson R, Sherman RL, Anderson RN, Henley SJ, Kohler BA, Penberthy L, Feuer EJ, Weir HK. Annual Report to the Nation on the Status of Cancer, 1975-2014, Featuring Survival. J Natl Cancer Inst. 2017 Sep 01;109(9) [PMC free article] [PubMed]
Jiang M, Liu F, Xiong WJ, Zhong L, Xu W, Xu F, et al. Combined MELD and blood lipid level in evaluating the prognosis of decompensated cirrhosis. World J Gastroenterol 2010; 16:1397–1401.
Luch, A. (2005). The carcinogenic effects of environmental factors. Mutation Research/Reviews in Mutation Research, 589(1), 23–35. [DOI: 10.1016/j.mrrev.2005.03.002].
Mansour, D. F., Abdallah, H. M., Ibrahim, B. M., Hegazy, R. R., Esmail, R. S. and Abdel-Salam, L. O. (2019). The carcinogenic agent diethylnitrosamine induces early oxidative stress, inflammation and proliferation in rat liver, stomach and colon: protective effect of ginger extract. Asian Pacific journal of cancer prevention: APJCP, 20(8), 2551
Musa, D. D., Anakaa, T. M. and Bashir, K. A. (2017). Phytochemical analysis of crude extracts from Annona senegalese (L) and its anti-snake venom potential on albino rats. Fudma journal of Sciences, 1(1), 139-142.
Napolitano M, Giuliani A, Alonzi T, Mancone C, D’Offizi G, Tripodi M, et al. Very low-density lipoprotein and low-density lipoprotein isolated from patients with hepatitis C infection induce altered cellular lipid metabolism. J Med Virol 2007; 79:254– 258.
Nashaat EH. Comparative study of serum lipid profile between chronic hepatitis C Egyptian patients and normal controls and the effect of viral eradication on lipids profile. Report Opinion 2010; 2:14–20.
Okhale, S. E., Akpan, E., Fatokun, O. T., Esievo, K. B. and Kunle, O. F. (2016). Annona senegalese Persoon (Annonaceae): A review of its ethnomedicinal uses, biological activities and phytocompounds. Journal of Pharmacognosy and Phytochemistry, 5(2), 211-219.
Okhale, S. E., Akpan, E., Fatokun, O. T., Esievo, K. B. and Kunle, O. F. (2016). Annona senegalese Persoon (Annonaceae): A review of its ethnomedicinal uses, biological activities and phytocompounds. Journal of Pharmacognosy and Phytochemistry, 5(2), 211-219.
Pogribny, I. P., & Rusyn, I. (2013). Role of epigenetic alterations in DEN-induced liver carcinogenesis. Toxicological Sciences, 135(2), 291-299.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646– 649.
Romeiras, M. M., Duarte, M. C., Francisco-Ortega, J., Catarino, L. and Havik, P. (2018). Recovering plant data for guinea-bissau: implications for biodiversity knowledge of West Africa. Diversity, 10(4), 109.
Sayiner, M., Golabi, P. and Younossi, Z. M. (2019). Disease burden of hepatocellular carcinoma: a global perspective. Digestive diseases and sciences, 64, 910-917.
Selimoglu MA, Aydogdu S, Yagci RV. Lipid parameters in childhood cirrhosis and chronic liver disease. Pediatr Int 2002. 44(4): 400-403
Sies, H., & Jones, D. P. (2007). Oxidative Stress and Antioxidant Defense: The Redox Code. Antioxidants & Redox Signaling, 9(7), 2071–2083. [DOI: 10.1089/ars.2007.1766]
Studenik P. Lipid disorders in liver diseases. VnitrLek 2000; 46:547–548.
Tolba, R., Kraus, T., Liedtke, C., Schwarz, M. and Weiskirchen, R. (2015). Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. Laboratory animals, 49(1), 59-69.
Tsai MH, Peng YS, Chen YC, Lien JM, Tian YC, Fang JT, et al. Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. J Hepatol 2009; 50:906–915.
Unsal, V. and Belge-Kurutaş, E. (2017). Experimental hepatic carcinogenesis: oxidative stress and natural antioxidants. Open Access Macedonian Journal of Medical Sciences, 5(5), 686.
Xu, X., Lei, Y., Chen, L., Zhou, H., Liu, H., Jiang, J. and Wu, B. (2021). Phosphorylation of NF-κBp65 drives inflammation-mediated hepatocellular carcinogenesis and is a novel therapeutic target. Journal of Experimental & Clinical Cancer Research, 40(1), 253.
You, Y., Zhu, F., Li, Z., Zhang, L., Xie, Y., Chinnathambi, A. and Lu, B. (2021). Phyllanthin prevents diethylnitrosamine (DEN) induced liver carcinogenesis in rats and induces apoptotic cell death in HepG2 cells. Biomedicine & Pharmacotherapy, 137, 111335.
Zhang, J., Shen, W., & Li, Y. (2019). High-fat diet exacerbates DEN-induced hepatocellular carcinoma. Hepatology, 70(5), 1623-1635.