In-depth hepatoprotective mechanistic study of Phyllanthus niruri: In vitro and in vivo studies and its chemical characterization

Autoři: Marwa I. Ezzat aff001;  Mona M. Okba aff001;  Sherif H. Ahmed aff002;  Hossny A. El-Banna aff003;  Abdelbary Prince aff004;  Shanaz O. Mohamed aff005;  Shahira M. Ezzat aff001
Působiště autorů: Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, Egypt aff001;  Department of Biochemistry, Faculty of Agriculture, Cairo University, Giza, Egypt aff002;  Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt aff003;  Department of Biochemistry, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt aff004;  School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia aff005;  Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226185


Phyllanthus niruri L. is a widespread tropical plant which is used in Ayurvedic system for liver and kidney ailments. The present study aims at specifying the most active hepatoprotective extract of P. niruri and applying a bio-guided protocol to identify the active compounds responsible for this effect. P. niruri aerial parts were extracted separately with water, 50%, 70% and 80% ethanol. The cytoprotective activity of the extracts was evaluated against CCl4-induced hepatotoxicity in clone-9 and Hepg2 cells. Bioassay-guided fractionation of the aqueous extract (AE) was accomplished for the isolation of the active compounds. Antioxidant activity was assessed using DPPH (1, 1-diphenyl-2-picrylhydrazyl) radical scavenging method and ferric reducing antioxidant power (FRAP). The in vivo hepatoprotective activity of AE was evaluated in CCl4-induced hepatotoxicity in rats at different doses after determination of its LD50. Pretreatment of clone-9 and Hepg2 with different concentrations of AE (1, 0.1, 0.01 mg/ml) had significantly reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) against CCl4 injures, and restored the activity of the natural antioxidants; glutathione (GSH) and superoxide dismutase (SOD) towards normalization. Fractionation of AE gave four fractions (I-IV). Fractions I, II, and IV showed a significant in vitro hepatoprotective activity. Purification of I, II and IV yielded seven compounds; corilagin C1, isocorilagin C2, brevifolin C3, quercetin C4, kaempferol rhamnoside C5, gallic acid C6, and brevifolin carboxylic acid C7. Compounds C1, C2, C5, and C7 showed the highest (p< 0.001) hepatoprotective potency, while C3, C4, and C6 exhibited a moderate (p< 0.001) activity. The AE exhibited strong antioxidant DPPH (IC50 11.6 ± 2 μg/ml) and FRAP (79.352 ± 2.88 mM Ferrous equivalents) activity. In vivo administration of AE in rats (25, 50, 100 and 200 mg/kg) caused normalization of AST, ALT, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total cholesterol (TC), triglycyrides (TG), total bilirubin (TB), glucose, total proteins (TP), urea and creatinine levels which were elevated by CCl4. AE also decreased TNF-α, NF-KB, IL-6, IL-8, IL10 and COX-2 expression, and significantly antagonizes the effect of CCl4 on the antioxidant enzymes SOD, catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GSP). The histopathological study also supported the hepatoprotective effect of AE. P. niruri isolates exhibited a potent hepatoprotective activity against CCl4-induced hepatotoxicity in clone-9 and Hepg2 cell lines through reduction of lipid peroxidation and maintaining glutathione in its reduced form. This is attributable to their phenolic nature and hence antioxidative potential.

Klíčová slova:

Antioxidants – Fractionation – Glutathione – Inflammation – Lipid peroxidation – Nitric oxide – Toxicity – Carboxylic acids


1. De Abajo FJ, Montero D, Madurga M, Garcia Rodriguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58(1):71–80. Epub 2004/06/23. doi: 10.1111/j.1365-2125.2004.02133.x 15206996; PubMed Central PMCID: PMC1884531.

2. Hoek JB, Pastorino JG. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol. 2002;27(1):63–8. doi: 10.1016/s0741-8329(02)00215-x 12062639

3. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci. 2002;65(2):166–76. Epub 2002/01/29. doi: 10.1093/toxsci/65.2.166 11812920.

4. Orhan DD, Orhan N, Ergun E, Ergun F. Hepatoprotective effect of Vitis vinifera L. leaves on carbon tetrachloride-induced acute liver damage in rats. Journal of Ethnopharmacology. 2007;112(1):145–51. doi: 10.1016/j.jep.2007.02.013 17391882

5. Jain NK, Lodhi S, Jain A, Nahata A, Singhai AK. Effects of Phyllanthus acidus (L.) Skeels fruit on carbon tetrachloride-induced acute oxidative damage in livers of rats and mice. Zhong Xi Yi Jie He Xue Bao. 2011;9(1):49–56. Epub 2011/01/14. doi: 10.3736/jcim20110109 21227033.

6. McGregor D, Lang M. Carbon tetrachloride: Genetic effects and other modes of action. Mutation Research/Reviews in Genetic Toxicology. 1996;366(3):181–95.

7. Edwards MJ, Keller BJ, Kauffman FC, Thurman RG. The involvement of Kupffer cells in carbon tetrachloride toxicity. Toxicol Appl Pharmacol. 1993;119(2):275–9. Epub 1993/04/01. doi: 10.1006/taap.1993.1069 8480336.

8. Recknagel RO, Glende EA Jr, Dolak JA, Waller RL. Mechanisms of carbon tetrachloride toxicity. Pharmacology & Therapeutics. 1989;43(1):139–54.

9. Calixto JB, Santos AR, Cechinel Filho V, Yunes RA. A review of the plants of the genus Phyllanthus: their chemistry, pharmacology, and therapeutic potential. Med Res Rev. 1998;18(4):225–58. Epub 1998/07/17. doi: 10.1002/(sici)1098-1128(199807)18:4<225::aid-med2>;2-x 9664291.

10. Pramyothin P, Ngamtin C, Poungshompoo S, Chaichantipyuth C. Hepatoprotective activity of Phyllanthus amarus Schum. et. Thonn. extract in ethanol treated rats: in vitro and in vivo studies. J Ethnopharmacol. 2007;114(2):169–73. Epub 2007/09/18. doi: 10.1016/j.jep.2007.07.037 17870264.

11. Khatoon S, Rai V, Rawat AK, Mehrotra S. Comparative pharmacognostic studies of three Phyllanthus species. J Ethnopharmacol. 2006;104(1–2):79–86. Epub 2005/10/21. doi: 10.1016/j.jep.2005.08.048 16236476.

12. Asha VV, Akhila S, Wills PJ, Subramoniam A. Further studies on the antihepatotoxic activity of Phyllanthus maderaspatensis Linn. J Ethnopharmacol. 2004;92(1):67–70. Epub 2004/04/22. doi: 10.1016/j.jep.2004.02.005 15099850.

13. Bagalkotkar G, Sagineedu SR, Saad MS, Stanslas J. Phytochemicals from Phyllanthus niruri Linn. and their pharmacological properties: a review. The Journal of pharmacy and pharmacology. 2006;58(12):1559–70. Epub 2007/03/03. doi: 10.1211/jpp.58.12.0001 17331318.

14. Bilal C. Healing in Urology: Clinical Guidebook to Herbal and Alternative Therapies: World Scientific; 2016.

15. Hiraganahalli BD, Chinampudur VC, Dethe S, Mundkinajeddu D, Pandre MK, Balachandran J, et al. Hepatoprotective and antioxidant activity of standardized herbal extracts. Pharmacogn Mag. 2012;8(30):116–23. Epub 2012/06/16. doi: 10.4103/0973-1296.96553 22701284; PubMed Central PMCID: PMC3371432.

16. Tatiya AU, Surana SJ, Sutar MP, Gamit NH. Hepatoprotective effect of poly herbal formulation against various hepatotoxic agents in rats. Pharmacognosy Res. 2012;4(1):50–6. Epub 2012/01/10. doi: 10.4103/0974-8490.91040 22224062; PubMed Central PMCID: PMC3250040.

17. Syamasundar KV, Singh B, Thakur RS, Husain A, Kiso Y, Hikino H. Antihepatotoxic principles of Phyllanthus niruri herbs. J Ethnopharmacol. 1985;14(1):41–4. Epub 1985/09/01. doi: 10.1016/0378-8741(85)90026-1 4087921.

18. Sabir SM, Rocha JBT. Water-extractable phytochemicals from Phyllanthus niruri exhibit distinct in vitro antioxidant and in vivo hepatoprotective activity against paracetamol-induced liver damage in mice. Food Chemistry. 2008;111(4):845–51. doi: 10.1016/j.foodchem.2008.04.060

19. Bhattacharjee R, Sil PC. Protein isolate from the herb, Phyllanthus niruri L. (Euphorbiaceae), plays hepatoprotective role against carbon tetrachloride induced liver damage via its antioxidant properties. Food Chem Toxicol. 2007;45(5):817–26. Epub 2006/12/19. doi: 10.1016/j.fct.2006.10.029 17175085.

20. Harish R, Shivanandappa T. Antioxidant activity and hepatoprotective potential of Phyllanthus niruri. Food Chemistry. 2006;95(2):180–5. doi: 10.1016/j.foodchem.2004.11.049

21. Murugaiyah V, Chan K-L. Mechanisms of antihyperuricemic effect of Phyllanthus niruri and its lignan constituents. Journal of Ethnopharmacology. 2009;124(2):233–9. doi: 10.1016/j.jep.2009.04.026 19397979

22. Khanna AK, Rizvi F, Chander R. Lipid lowering activity of Phyllanthus niruri in hyperlipemic rats. Journal of Ethnopharmacology. 2002;82(1):19–22. doi: 10.1016/s0378-8741(02)00136-8 12169400

23. Manjrekar AP, Jisha V, Bag PP, Adhikary B, Pai MM, Hegde A, et al. Effect of Phyllanthus niruri Linn. treatment on liver, kidney and testes in CCl4 induced hepatotoxic rats. Indian J Exp Biol. 2008;46(7):514–20. Epub 2008/09/24. 18807755.

24. Pareek A, Godavarthi A, Issarani R, Nagori BP. Antioxidant and hepatoprotective activity of Fagonia schweinfurthii (Hadidi) Hadidi extract in carbon tetrachloride induced hepatotoxicity in HepG2 cell line and rats. Journal of ethnopharmacology. 2013;150(3):973–81. doi: 10.1016/j.jep.2013.09.048 24140589

25. Shimada K, Fujikawa K, Yahara K, Nakamura T. Antioxidative properties of xanthan on the autoxidation of soybean oil in cyclodextrin emulsion. Journal of agricultural and food chemistry. 1992;40(6):945–8.

26. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Analytical biochemistry. 1996;239(1):70–6. doi: 10.1006/abio.1996.0292 8660627

27. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978;86(1):271–8. Epub 1978/05/01. 0003-2697(78)90342-1 [pii]. doi: 10.1016/0003-2697(78)90342-1 655387.

28. Ellman GL. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics. 1959;82(1):70–7. doi: 10.1016/0003-9861(59)90090-6 13650640

29. LeBel CP, Ischiropoulos H, Bondy SC. Evaluation of the probe 2', 7'-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chemical research in toxicology. 1992;5(2):227–31. doi: 10.1021/tx00026a012 1322737

30. Miranda KM, Espey MG, Wink DA. A Rapid, Simple Spectrophotometric Method for Simultaneous Detection of Nitrate and Nitrite. Nitric Oxide. 2001;5(1):62–71. doi: 10.1006/niox.2000.0319 11178938

31. Nawwar MA, Hussein SA, Merfort I. NMR spectral analysis of polyphenols from Punica granatum. Phytochemistry. 1994;36(3):793–8.

32. Habib-ur-Rehman, Yasin KA, Choudhary MA, Khaliq N, Atta-ur-Rahman, Choudhary MI, et al. Studies on the chemical constituents of Phyllanthus emblica. Natural Product Research. 2007;21(9):775–81. doi: 10.1080/14786410601124664 17763100

33. Zhang L-Z, Guo Y, Tu G, Guo W, Miao F. Studies on chemical constituents of Phyllanthus urinaria L. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2000;25(10):615–7. 12516452

34. Krithika R, Mohankumar R, Verma RJ, Shrivastav PS, Mohamad IL, Gunasekaran P, et al. Isolation, characterization and antioxidative effect of phyllanthin against CCl4-induced toxicity in HepG2 cell line. Chemico-biological interactions. 2009;181(3):351–8. Epub 2009/07/07. doi: 10.1016/j.cbi.2009.06.014 19576190.

35. Sprenger RF, Thomasi SS, Ferreira AG, Cass QB, Batista Junior JM. Solution-state conformations of natural products from chiroptical spectroscopy: the case of isocorilagin. Organic & biomolecular chemistry. 2016;14(13):3369–75. Epub 2016/03/08. doi: 10.1039/c6ob00049e 26946940.

36. Gulati RK, Agarwal S, Agrawal SS. Hepatoprotective studies on Phyllanthus emblica Linn. and quercetin. Indian journal of experimental biology. 1995;33(4):261–8. Epub 1995/04/01. 7558182.

37. Rasool MK, Sabina EP, Ramya SR, Preety P, Patel S, Mandal N, et al. Hepatoprotective and antioxidant effects of gallic acid in paracetamol-induced liver damage in mice. The Journal of pharmacy and pharmacology. 2010;62(5):638–43. Epub 2010/07/09. doi: 10.1211/jpp.62.05.0012 20609067.

38. Kinoshita S, Inoue Y, Nakama S, Ichiba T, Aniya Y. Antioxidant and hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa Island and its tannin corilagin. Phytomedicine: international journal of phytotherapy and phytopharmacology. 2007;14(11):755–62. Epub 2007/02/13. doi: 10.1016/j.phymed.2006.12.012 17293097.

39. Janakat S, Al-Merie H. Optimization of the dose and route of injection, and characterisation of the time course of carbon tetrachloride-induced hepatotoxicity in the rat. Journal of Pharmacological and Toxicological Methods. 2002;48(1):41–4. doi: 10.1016/S1056-8719(03)00019-4 12750040

40. Smejkalova J, Simek J, Rouchal J, Dvorackova I. The time course of biochemical and histological changes following carbon tetrachloride-induced liver damage in rats of both sexes. Physiol Bohemoslov. 1985;34(6):494–501. Epub 1985/01/01. 2868469.

41. Rees KR, Sinha KP. Blood enzymes in liver injury. J Pathol Bacteriol. 1960;80:297–307. Epub 1960/10/01. 13740296.

42. Rhiouani H, Settaf A, Lyoussi B, Cherrah Y, Lacaille-Dubois MA, Hassar M. Effects of saponins from Herniaria glabra on blood pressure and renal function in spontaneously hypertensive rats. Therapie. 1999;54(6):735–9. Epub 2000/03/10. 10709449.

43. Horn HJ. Simplified LD50 (or ED50) Calculations. Biometrics. 1956;12(3):311–22.

44. Amacher DE. Serum Transaminase Elevations as Indicators of Hepatic Injury Following the Administration of Drugs. Regulatory Toxicology and Pharmacology. 1998;27(2):119–30. doi: 10.1006/rtph.1998.1201 9671567

45. Sturgill MG, Lambert GH. Xenobiotic-induced hepatotoxicity: mechanisms of liver injury and methods of monitoring hepatic function. Clin Chem. 1997;43(8 Pt 2):1512–26. Epub 1997/08/01. 9265903.

46. Breikaa RM, Algandaby MM, El-Demerdash E, Abdel-Naim AB. Biochanin A protects against acute carbon tetrachloride-induced hepatotoxicity in rats. Bioscience, biotechnology, and biochemistry. 2013;77(5):909–16. doi: 10.1271/bbb.120675 23649249

47. Säemann MD, Poglitsch M, Kopecky C, Haidinger M, Hörl WH, Weichhart T. The versatility of HDL: a crucial anti‐inflammatory regulator. European journal of clinical investigation. 2010;40(12):1131–43. doi: 10.1111/j.1365-2362.2010.02361.x 20695882

48. Khanna A, Rizvi F, Chander R. Lipid lowering activity of Phyllanthus niruri in hyperlipemic rats. Journal of ethnopharmacology. 2002;82(1):19–22. doi: 10.1016/s0378-8741(02)00136-8 12169400

49. Mehendale H, Roth R, Gandolfi AJ, Klaunig J, Lemasters J, Curtis L. Novel mechanisms in chemically induced hepatotoxicity. The FASEB journal. 1994;8(15):1285–95. doi: 10.1096/fasebj.8.15.8001741 8001741

50. Kalekar SA, Munshi RP, Thatte UM. Do plants mediate their anti-diabetic effects through anti-oxidant and anti-apoptotic actions? an in vitro assay of 3 Indian medicinal plants. BMC complementary and alternative medicine. 2013;13(1):257.

51. Tewari D, Mocan A, Parvanov ED, Sah AN, Nabavi SM, Huminiecki L, et al. Ethnopharmacological approaches for therapy of jaundice: Part II. Highly used plant species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae families. Front Pharmacol. 2017;8:519. doi: 10.3389/fphar.2017.00519 28848436

52. Lykkesfeldt J. Malondialdehyde as biomarker of oxidative damage to lipids caused by smoking. Clinica Chimica Acta. 2007;380:50–8.

53. Matés JM, Pérez-Gómez C, De Castro IN. Antioxidant enzymes and human diseases. Clinical Biochemistry. 1999;32(8):595–603. doi: 10.1016/s0009-9120(99)00075-2 10638941

54. Fang Y-Z, Yang S, Wu G. Free radicals, antioxidants, and nutrition. Nutrition. 2002;18(10):872–9. doi: 10.1016/s0899-9007(02)00916-4 12361782

55. Fridovich I. Superoxide and superoxide dismutases. Free Radical Biology and Medicine. 1993;15(5):472.

56. Zhu R, Wang Y, Zhang L, Guo Q. Oxidative stress and liver disease. Hepatol Res. 2012. Epub 2012/04/12. doi: 10.1111/j.1872-034X.2012.00996.x 22489668.

57. Ramkumar KM, Rajesh R, Anuradha CV. Food restriction attenuates blood lipid peroxidation in carbon tetrachloride–intoxicated rats. Nutrition. 2003;19(4):358–62. doi: 10.1016/s0899-9007(02)00961-9 12679172

58. Hsu C-T. Ultrastructural changes in liver damage induced by carbon tetrachloride in spontaneously hypertensive rats and Wistar–Kyoto rats. Journal of the Autonomic Nervous System. 1998;70(1–2):79–83. doi: 10.1016/s0165-1838(98)00035-6 9686907

59. Smyth R, Munday MR, York MJ, Clarke CJ, Dare T, Turton JA. Dose response and time course studies on superoxide dismutase as a urinary biomarker of carbon tetrachloride-induced hepatic injury in the Hanover Wistar rat. Int J Exp Pathol. 2009;90(5):500–11. Epub 2009/09/22. IEP666 [pii] doi: 10.1111/j.1365-2613.2009.00666.x 19765104.

60. Popovic M, Janicijevic-Hudomal S, Kaurinovic B, Rasic J, Trivic S. Effects of various drugs on alcohol-induced oxidative stress in the liver. Molecules. 2008;13(9):2249–59. Epub 2008/10/03. 13092249 [pii]. doi: 10.3390/molecules13092249 18830154.

61. Di Simplicio P, Mannervik B. Enzymes involved in glutathione metabolism in rat liver and blood after carbon tetrachloride intoxication. Toxicology Letters. 1983;18(3):285–9. doi: 10.1016/0378-4274(83)90108-x 6665803

62. Yoko A, Akira N. Oxidative stress-induced activation of microsomal glutathione S-transferase in isolated rat liver. Biochemical Pharmacology. 1993;45(1):37–42. doi: 10.1016/0006-2952(93)90374-6 8424821

63. Ismail NA, Okasha SH, Dhawan A, Abdel-Rahman AO, Shaker OG, Sadik NA. Antioxidant enzyme activities in hepatic tissue from children with chronic cholestatic liver disease. Saudi J Gastroenterol. 2010;16(2):90–4. Epub 2010/03/27. doi: 10.4103/1319-3767.61234 20339177; PubMed Central PMCID: PMC3016512.

64. Beyer W, Imlay J, Fridovich I. Superoxide Dismutases. In: Waldo EC, Kivie M, editors. Progress in Nucleic Acid Research and Molecular Biology. Volume 40: Academic Press; 1991. p. 221–53. doi: 10.1016/s0079-6603(08)60843-0 1851570

65. Ishiyama H, Ogino K, Hobara T. Role of Kupffer cells in rat liver injury induced by diethyldithiocarbamate. Eur J Pharmacol. 1995;292(2):135–41. Epub 1995/01/13. doi: 10.1016/0926-6917(95)90005-5 7720785.

66. Colten HR. Tissue-specific regulation of inflammation. J Appl Physiol. 1992;72(1):1–7. Epub 1992/01/01. doi: 10.1152/jappl.1992.72.1.1 1371501.

67. DeCicco LA, Rikans LE, Tutor CG, Hornbrook KR. Serum and liver concentrations of tumor necrosis factor-α and interleukin-1β following administration of carbon tetrachloride to male rats. Toxicology Letters. 1998;98:115–21. doi: 10.1016/s0378-4274(98)00110-6 9776568

68. Lowenstein CJ, Snyder SH. Nitric oxide, a novel biologic messenger. Cell. 1992;70(5):705–7. Epub 1992/09/04. doi: 10.1016/0092-8674(92)90301-r 1381285.

69. Morio LA, Chiu H, Sprowles KA, Zhou P, Heck DE, Gordon MK, et al. Distinct roles of tumor necrosis factor-alpha and nitric oxide in acute liver injury induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol. 2001;172(1):44–51. Epub 2001/03/27. doi: 10.1006/taap.2000.9133 11264022.

70. Clemens MG. Nitric oxide in liver injury. Hepatology. 1999;30(1):1–5. Epub 1999/07/01. S0270913999003018 [pii] doi: 10.1002/hep.510300148 10385631.

71. Rockey DC, Chung JJ. Regulation of inducible nitric oxide synthase and nitric oxide during hepatic injury and fibrogenesis. Am J Physiol. 1997;273(1 Pt 1):G124–30. Epub 1997/07/01. doi: 10.1152/ajpgi.1997.273.1.G124 9252518.

72. Vos TA, Van Goor H, Tuyt L, De Jager-Krikken A, Leuvenink R, Kuipers F, et al. Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status. Hepatology. 1999;29(2):421–6. Epub 1999/01/27. S0270913999000634 [pii] doi: 10.1002/hep.510290231 9918918.

73. Al-Shabanah OA, Alam K, Nagi MN, Al-Rikabi AC, Al-Bekairi AM. Protective effect of aminoguanidine, a nitric oxide synthase inhibitor, against carbon tetrachloride induced hepatotoxicity in mice. Life Sci. 2000;66(3):265–70. Epub 2000/02/09. S0024320599005895 [pii]. doi: 10.1016/s0024-3205(99)00589-5 10666002.

74. Chamulitrat W, Jordan SJ, Mason RP. Nitric oxide production during endotoxic shock in carbon tetrachloride-treated rats. Mol Pharmacol. 1994;46(2):391–7. Epub 1994/08/01. 8078502.

75. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2. J Biol Chem. 1996;271(52):33157–60. Epub 1996/12/27. doi: 10.1074/jbc.271.52.33157 8969167.

76. Hu K-Q. Cyclooxygenase 2 (COX2)-prostanoid pathway and liver diseases. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2003;69(5):329–37. doi: 10.1016/j.plefa.2003.07.001 14580367

77. Zhu W, Fung PC. The roles played by crucial free radicals like lipid free radicals, nitric oxide, and enzymes NOS and NADPH in CCl(4)-induced acute liver injury of mice. Free Radic Biol Med. 2000;29(9):870–80. Epub 2000/11/07. S0891-5849(00)00396-8 [pii]. doi: 10.1016/s0891-5849(00)00396-8 11063912.

78. Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, et al. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology. 1998;27(3):748–54. Epub 1998/03/21. S0270913998001104 [pii] doi: 10.1002/hep.510270316 9500703.

79. Lee NY, Khoo WK, Adnan MA, Mahalingam TP, Fernandez AR, Jeevaratnam K. The pharmacological potential of Phyllanthus niruri. Journal of pharmacy and pharmacology. 2016;68(8):953–69. doi: 10.1111/jphp.12565 27283048

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