Ethanolic extract of stems of Gnetum ula Brongn ameliorates carbon tetrachloride induced liver toxicity in wistar rats

Sharath Rajshekarappa; Preetham Jinadatta; Kiran Sundera; Sujan Ganapathy Pasura Subbaiah; Sivakami Sundari Ponnusamy; Mruthunjaya Kenganora

doi:10.7324/JAPS.2025.157972

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Abstract

Gnetum ula is used to cure several disorders, whereas stem is used for treating jaundice. The goal of this study is to assess the ethanolic extract of stems of G. ula for in vivo hepatoprotective and antioxidant efficacy against hepatotoxicity caused by carbon tetrachloride. Wistar rats were employed in the investigation, and silymarin was used as the reference drug to assess liver function tests in CCl4-treated and untreated groups. Antioxidant enzyme systems involving CAT, GSH, SOD, and malondialdehyde levels were examined. Histopathology studies were carried out. Ethanolic stem extract of G. ula (200 mg/kg) blocked the CCl4-induced elevation of biochemical markers levels of AST (154.5 ± 24.0 IU/l), ALT (125.9 ± 3.5 IU/l), alkaline phosphatase (177.1 ± 3.8IU/l), and total bilirubin (1.06 ± 0.1 g/dl). Total protein (6.86 ± 0.1 g/dl) and albumin (4.23 ± 0.7 g/dl) was also increased in ethanolic stem extract-treated animals. A significant decline in the CAT, SOD, GSH, and elevation in MDA levels was observed in CCl4-intoxicated animals. Antioxidant enzyme levels in plant extract-treated groups were comparable to standard and normal. The present report of ethanolic stem extract of G. ula in shielding the liver from adverse effects of CCl4 supports the traditional use to cure liver disease and has been reported foremost.

Keyword: Hepatoprotective CCl4 Gnetum ulam antioxidant

Citation:

Rajshekarappa S, Jinadatta P, Sundera K, Subbaiah SGP, Ponnusamy SS, Kenganora M. Ethanolic extract of stems of Gnetum ula Brongn ameliorates carbon tetrachloride induced liver toxicity in wistar rats. J Appl Pharm Sci. 2025. Online first. http://doi.org/10.7324/JAPS.2025.157972

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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3. Maity T, Maity S, Pahari N, Ranjan DK, Ganguli S. A review on hepatic diseases and development of herbal drugs for the treatment of liver complications. World J Pharm Res. 2015;5(5):677-91.
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5. Thirumalian T, Elumalai EK, Viviyan TS, Senthil BK, Ernest. D. Ethnobotanical survey of folklore plants for the treatment of jaundice and snakebites in vellore. J Ethnobot Leaflets. 2010;14:529-36.
6. Mohan VR, Rajesh A, Athiperumalsami T, Sutha S. Ethnomedicinal plants of the Tirunelveli District. Tamilnadu, India. J Ethnobot Leaflets. 2008;12:79-95.
7. Pushpangadan P, Atal CK. Ethnomedical and ethnobotanical investigations among some scheduled caste communities of Travancore, Kerala. India. J Ethnopharmacol. 1986;16(1-2):175-90. https://doi.org/10.1016/0378-8741(86)90088-7
8. Raj Kumar MH, Rajanna MD. Ex-situ conservation of climbing plants at university of agricultural sciences, Bangalore, Karnataka. Rec Res Sci Tech. 2011;3(4):18-20.
9. Basu P, Mitra B. Preliminary notes on the climbing taxa of Andaman and Nicobar Islands with special reference to their importance. J Econ Taxon Bot. 1992;16:393-9.
10. Pullaiah. T. Biodiversity of India. Paris, France: Regency publications; 1992. Pp 552.
11. Prusti AB, Behera KK. Ethnobotanical exploration of Malkangiri District of Orissa, India. J Ethnobot Leaflets. 2007;11:122-40.
12. Warrier PK, Nambiar VPK, Ramankutty C. Indian medicinal plants: a compendium of 500 species. Madras, India: Orient Longman; 1993.
13. Mondal P, Mukerjee PK. Notes on ethnobotany of Keonjhar district, Orissa. J Econ Tax Bot Addl Ser. 1992;10:7-18.
14. Zaman A, Prakash S, Wizarat. K. Isolation and structure of gnetol, a novel stilbene from Gnetum ula. Indian J Chem. 1983;22b:101-4.
15. Prakash S, Khan MA, Khan KZ. Stilbenes of Gnetum Ula. Phytochemistry. 1985;24:622-4. https://doi.org/10.1016/S0031-9422(00)80789-X
16. Siddiqui Z, Rahman S, Khan MA. Gnetulin, a dimer of 3',4,5' - Trihydoxy- 3- methoxy Stilbene from Gnetum ula. Tetrahedron. 1993;49:10393-6. https://doi.org/10.1016/S0040-4020(01)80565-2
17. Tandon N. Reviews on Indian medicinal Plants. Medicinal Plant Unit, Indian Council of Medical Research, New Delhi. 2013;11:1120.
18. Khandewal KR. Practical pharmacognosy. 22nd ed. Pune, India: Nirali publications; 2013.
19. OECD/OCDE. OECD Guideline for testing of chemicals. Acute Oral Toxicity-Acute Toxicity Class methods. Paris, France: OECD Publishing; 2002.
20. Chen Y, Huang B, He J, Han L, Zhan Y, Wang Y. In vitro and in vivo antioxidant effects of the ethanolic extract of Swertia chiraytia. J Ethnopharmacol. 2011;136(2):309-15. https://doi.org/10.1016/j.jep.2011.04.058
21. Pareek A, Godvarthi A, Issarani R, Nagori BP. Antioxidant and hepatoprotective activity of Fagonia schweinfurthii (Hadidi) extract in carbon tetrachloride induced hepatotoxicity in HepG2 cell line and rats. J Ethnopharmacol. 2013;150(3):973-81. https://doi.org/10.1016/j.jep.2013.09.048
22. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobartituric acid reaction Anal. Biochem. 1979;95(2):351-58. https://doi.org/10.1016/0003-2697(79)90738-3
23. Mishra HP, Fridovich I. The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170-5. https://doi.org/10.1016/S0021-9258(19)45228-9
24. Aebi H. Catalase. In: Bergmeyer HV. Methods in enzymatic analysis Newyork, NY: Academic press; 1974. Vol. 2, pp 674-84. https://doi.org/10.1016/B978-0-12-091302-2.50032-3
25. Moran MA, Depierre JW, Mannervick B. Levels of glutathione, glutathione reductase, glutathione-S-transferase activities in rat liver. Biochimica Biophysica Acta. 1979;582(1):67-8. https://doi.org/10.1016/0304-4165(79)90289-7
26. Shenoy, KA, Somayaji SN, Bairy KL. Hepatoprotective effects of Ginkgo biloba against carbon tetrachloride induced hepatic injury in rats. Indian J Pharmacol. 2001;33(4):260-6.
27. Ames BN, Shigenenga MT, Hagen M. Oxidants, antioxidants and the degenerative diseases of aging. Proc Natl Acad Sci United States Am. 1993;90(3):7915-22. https://doi.org/10.1073/pnas.90.17.7915
28. Cameron GR, Karunaratne WAE. Carbon tetrachloride cirrhosis in relation to liver regeneration. J Pathol Bacteriol. 1936;42(1):1-21. https://doi.org/10.1002/path.1700420104
29. Thabrew MI, Joice PD, Rajatissa WA. Comparative study of the efficacy of Paetta indica and Osbeckia octandra in the treatment of liver dysfunction. Planta Med. 1987;53(3):239-41. https://doi.org/10.1055/s-2006-962691
30. Bishayee A, Sarkar A, Chaterjee M. The hepatoprotective activity of carrot (Daucas carota L.) against carbon tetrachloride intoxication in mouse liver. J Ethnopharmacol. 1995;49(2):69-74. https://doi.org/10.1016/0378-8741(95)01254-B
31. Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI. Role of pro-inflammatory cytokines in acetaminophen hepatoxicity. Toxicol Appl Pharmacol. 1995;133(1):43-52. https://doi.org/10.1006/taap.1995.1125
32. Bourdi M, Masubuchi Y, Rreilly TP. Protection against acetaminophen -induced liver injury and lethality by interleukin 10, role of inducible nitric oxide synthase. Hepatology. 2002;35(2):289-98. https://doi.org/10.1053/jhep.2002.30956
33. Molander DWF, Wrolewski, JS. LA-Due. Transaminase compared with cholesterase and alkaline phosphatase an index of hepatocellular intergrity. Clin Res Proc. 1987;3:20-4.
34. Harsha Mohan. The liver, biliary tract and exocrine pancreas. In: Text book of pathology, 4th ed. New Delhi, India: Jaypee Brothers Medical Publishers LTD; 2002. Pp 447-9.
35. Victor J, Navarro MD, John R, Senior MD. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-39. https://doi.org/10.1056/NEJMra052270
36. Goel A, Dani.V, Dhawan DK. Protective effects of zinc on lipid peroxidation, antioxidation, antioxidant enzymes and hepatic histoarchitecture in chlorphrifos induced toxicity. Chem Biol Interact. 2005;156(2-3):131-40. https://doi.org/10.1016/j.cbi.2005.08.004
37. Wu YH, Zhang XM, Hu MH, Wu XM, Zhao Y. Effect of Lagera alata on hepatocytes damage induced by carbon tetrachloride in vitro and in vivo. J Ethnopharmacol. 2009;126(1):50-6. https://doi.org/10.1016/j.jep.2009.08.030
38. Velioglu YS, Mazza G, Gao L, Oomah BD. Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. J Agric Food Chem. 1998;46:4113-7. https://doi.org/10.1021/jf9801973
39. Sevindik M, Akgul H, Pehlivan M, Selamoglu Z. Determination of therapeutic potential of Mentha longifolia ssp. longifolia. Fresen Environ Bull. 2017;26(7):4757-63.
40. Antonio A, Mario F. Muñoz, Sandro Argüelles. "Lipid Peroxidation: production, metabolism, and signaling mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal". Oxid Med Cell Longev. 2014;2014:31. https://doi.org/10.1155/2014/360438
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42. Pereira DM, Valentão P, José AP, Andrade PB. Phenolics: from chemistry to biology. Molecules. 2009;14(6):2202-11. https://doi.org/10.3390/molecules14062202
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44. Tanaka T, Iliya I, Ito T, Furusawa M, Nakaya KI, Iinuma M, et al. Stilbenoids in Lianas of Gnetum parvifolium. Chem Pharm Bull. 2001;49(7):858-62. https://doi.org/10.1248/cpb.49.858
45. Tao S, Wang XN, Lou HX. Natural stilbenes: an overview. Nat Prod Rep. 2009;26:916-35. https://doi.org/10.1039/b905960a

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1. Negi AS, Kumar JK, Luqman S, Shanker K, Gupta MM, Khanuja SP. Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads. Med Res Rev. 2008;28(5):746-72. https://doi.org/10.1002/med.20115

2. Ali AM, Alan DL, Saied S, Rafael L, Ali HM, Jeff S, et al. Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med. 2014;12(1):145. https://doi.org/10.1186/s12916-014-0145-y

3. Maity T, Maity S, Pahari N, Ranjan DK, Ganguli S. A review on hepatic diseases and development of herbal drugs for the treatment of liver complications. World J Pharm Res. 2015;5(5):677-91.

4. Vikneshwaran D, Viji M, Raja LK. Ethanomedicinal plants survey and documentation related to paliyar community. J Ethnobot Leaflets. 2008;12(1):1108-11015.

5. Thirumalian T, Elumalai EK, Viviyan TS, Senthil BK, Ernest. D. Ethnobotanical survey of folklore plants for the treatment of jaundice and snakebites in vellore. J Ethnobot Leaflets. 2010;14:529-36.

6. Mohan VR, Rajesh A, Athiperumalsami T, Sutha S. Ethnomedicinal plants of the Tirunelveli District. Tamilnadu, India. J Ethnobot Leaflets. 2008;12:79-95.

7. Pushpangadan P, Atal CK. Ethnomedical and ethnobotanical investigations among some scheduled caste communities of Travancore, Kerala. India. J Ethnopharmacol. 1986;16(1-2):175-90. https://doi.org/10.1016/0378-8741(86)90088-7

8. Raj Kumar MH, Rajanna MD. Ex-situ conservation of climbing plants at university of agricultural sciences, Bangalore, Karnataka. Rec Res Sci Tech. 2011;3(4):18-20.

9. Basu P, Mitra B. Preliminary notes on the climbing taxa of Andaman and Nicobar Islands with special reference to their importance. J Econ Taxon Bot. 1992;16:393-9.

10. Pullaiah. T. Biodiversity of India. Paris, France: Regency publications; 1992. Pp 552.

11. Prusti AB, Behera KK. Ethnobotanical exploration of Malkangiri District of Orissa, India. J Ethnobot Leaflets. 2007;11:122-40.

12. Warrier PK, Nambiar VPK, Ramankutty C. Indian medicinal plants: a compendium of 500 species. Madras, India: Orient Longman; 1993.

13. Mondal P, Mukerjee PK. Notes on ethnobotany of Keonjhar district, Orissa. J Econ Tax Bot Addl Ser. 1992;10:7-18.

14. Zaman A, Prakash S, Wizarat. K. Isolation and structure of gnetol, a novel stilbene from Gnetum ula. Indian J Chem. 1983;22b:101-4.

15. Prakash S, Khan MA, Khan KZ. Stilbenes of Gnetum Ula. Phytochemistry. 1985;24:622-4. https://doi.org/10.1016/S0031-9422(00)80789-X

16. Siddiqui Z, Rahman S, Khan MA. Gnetulin, a dimer of 3',4,5' - Trihydoxy- 3- methoxy Stilbene from Gnetum ula. Tetrahedron. 1993;49:10393-6. https://doi.org/10.1016/S0040-4020(01)80565-2

17. Tandon N. Reviews on Indian medicinal Plants. Medicinal Plant Unit, Indian Council of Medical Research, New Delhi. 2013;11:1120.

18. Khandewal KR. Practical pharmacognosy. 22nd ed. Pune, India: Nirali publications; 2013.

19. OECD/OCDE. OECD Guideline for testing of chemicals. Acute Oral Toxicity-Acute Toxicity Class methods. Paris, France: OECD Publishing; 2002.

20. Chen Y, Huang B, He J, Han L, Zhan Y, Wang Y. In vitro and in vivo antioxidant effects of the ethanolic extract of Swertia chiraytia. J Ethnopharmacol. 2011;136(2):309-15. https://doi.org/10.1016/j.jep.2011.04.058

21. Pareek A, Godvarthi A, Issarani R, Nagori BP. Antioxidant and hepatoprotective activity of Fagonia schweinfurthii (Hadidi) extract in carbon tetrachloride induced hepatotoxicity in HepG2 cell line and rats. J Ethnopharmacol. 2013;150(3):973-81. https://doi.org/10.1016/j.jep.2013.09.048

22. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobartituric acid reaction Anal. Biochem. 1979;95(2):351-58. https://doi.org/10.1016/0003-2697(79)90738-3

23. Mishra HP, Fridovich I. The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170-5. https://doi.org/10.1016/S0021-9258(19)45228-9

24. Aebi H. Catalase. In: Bergmeyer HV. Methods in enzymatic analysis Newyork, NY: Academic press; 1974. Vol. 2, pp 674-84. https://doi.org/10.1016/B978-0-12-091302-2.50032-3

25. Moran MA, Depierre JW, Mannervick B. Levels of glutathione, glutathione reductase, glutathione-S-transferase activities in rat liver. Biochimica Biophysica Acta. 1979;582(1):67-8. https://doi.org/10.1016/0304-4165(79)90289-7

26. Shenoy, KA, Somayaji SN, Bairy KL. Hepatoprotective effects of Ginkgo biloba against carbon tetrachloride induced hepatic injury in rats. Indian J Pharmacol. 2001;33(4):260-6.

27. Ames BN, Shigenenga MT, Hagen M. Oxidants, antioxidants and the degenerative diseases of aging. Proc Natl Acad Sci United States Am. 1993;90(3):7915-22. https://doi.org/10.1073/pnas.90.17.7915

28. Cameron GR, Karunaratne WAE. Carbon tetrachloride cirrhosis in relation to liver regeneration. J Pathol Bacteriol. 1936;42(1):1-21. https://doi.org/10.1002/path.1700420104

29. Thabrew MI, Joice PD, Rajatissa WA. Comparative study of the efficacy of Paetta indica and Osbeckia octandra in the treatment of liver dysfunction. Planta Med. 1987;53(3):239-41. https://doi.org/10.1055/s-2006-962691

30. Bishayee A, Sarkar A, Chaterjee M. The hepatoprotective activity of carrot (Daucas carota L.) against carbon tetrachloride intoxication in mouse liver. J Ethnopharmacol. 1995;49(2):69-74. https://doi.org/10.1016/0378-8741(95)01254-B

31. Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI. Role of pro-inflammatory cytokines in acetaminophen hepatoxicity. Toxicol Appl Pharmacol. 1995;133(1):43-52. https://doi.org/10.1006/taap.1995.1125

32. Bourdi M, Masubuchi Y, Rreilly TP. Protection against acetaminophen -induced liver injury and lethality by interleukin 10, role of inducible nitric oxide synthase. Hepatology. 2002;35(2):289-98. https://doi.org/10.1053/jhep.2002.30956

33. Molander DWF, Wrolewski, JS. LA-Due. Transaminase compared with cholesterase and alkaline phosphatase an index of hepatocellular intergrity. Clin Res Proc. 1987;3:20-4.

34. Harsha Mohan. The liver, biliary tract and exocrine pancreas. In: Text book of pathology, 4th ed. New Delhi, India: Jaypee Brothers Medical Publishers LTD; 2002. Pp 447-9.

35. Victor J, Navarro MD, John R, Senior MD. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-39. https://doi.org/10.1056/NEJMra052270

36. Goel A, Dani.V, Dhawan DK. Protective effects of zinc on lipid peroxidation, antioxidation, antioxidant enzymes and hepatic histoarchitecture in chlorphrifos induced toxicity. Chem Biol Interact. 2005;156(2-3):131-40. https://doi.org/10.1016/j.cbi.2005.08.004

37. Wu YH, Zhang XM, Hu MH, Wu XM, Zhao Y. Effect of Lagera alata on hepatocytes damage induced by carbon tetrachloride in vitro and in vivo. J Ethnopharmacol. 2009;126(1):50-6. https://doi.org/10.1016/j.jep.2009.08.030

38. Velioglu YS, Mazza G, Gao L, Oomah BD. Antioxidant activity and total phenolics in selected fruits, vegetables, and grain products. J Agric Food Chem. 1998;46:4113-7. https://doi.org/10.1021/jf9801973

39. Sevindik M, Akgul H, Pehlivan M, Selamoglu Z. Determination of therapeutic potential of Mentha longifolia ssp. longifolia. Fresen Environ Bull. 2017;26(7):4757-63.

40. Antonio A, Mario F. Muñoz, Sandro Argüelles. "Lipid Peroxidation: production, metabolism, and signaling mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal". Oxid Med Cell Longev. 2014;2014:31. https://doi.org/10.1155/2014/360438

41. Preetham J, Kiran S, Sharath R, Sundari S, Ganapathy S, Sushma S Murthy. Pharmacognostic and preliminary phytochemical studies in Gnetum ula brongn. Int Res J Pharm. 2015;6:377-38. https://doi.org/10.7897/2230-8407.06678

42. Pereira DM, Valentão P, José AP, Andrade PB. Phenolics: from chemistry to biology. Molecules. 2009;14(6):2202-11. https://doi.org/10.3390/molecules14062202

43. Lin M, Li JB, Li SZ, Yu DQ, Liang XT. A dimeric stilbene from Gnetum parvifolium. Phytochemistry. 1992;31(2):633-8. https://doi.org/10.1016/0031-9422(92)90050-Z

44. Tanaka T, Iliya I, Ito T, Furusawa M, Nakaya KI, Iinuma M, et al. Stilbenoids in Lianas of Gnetum parvifolium. Chem Pharm Bull. 2001;49(7):858-62. https://doi.org/10.1248/cpb.49.858

45. Tao S, Wang XN, Lou HX. Natural stilbenes: an overview. Nat Prod Rep. 2009;26:916-35. https://doi.org/10.1039/b905960a