The protective effect of Nigella sativa against liver injury: a review

Document Type: Review Article

Authors

1 Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Nigella sativa (Family Ranunculaceae) is a widely used medicinal plant throughout the world. N. sativa is referred in the Middle East as a part of an overall holistic approach to health. Pharmacological properties of N. sativa including immune stimulant, hypotensive, anti-inflammatory, anti-cancer, antioxidant, hypoglycemic, spasmolytic and bronchodilator have been shown. Reactive oxygen species (ROS) and oxidative stress are known as the major causes of many diseases such as liver injury and many substances and drugs can induce oxidative damage by generation of ROS in the body. Many pharmacological properties of N. sativa are known to be attributed to the presence of thymoquinone and its antioxidant effects. Thymoquinone protects liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and glutathione level, radical scavengering, increasing the activity of quinone reductase, catalase, superoxide dismutase and glutathione transferase, inhibition of NF-κB activity and inhibition of both cyclooxygenase and lipoxygenase. Therefore, this review aimed to highlight the roles of ROS in liver diseases and the mechanisms of N. sativa in prevention of liver injury.

Keywords


1. Shaikh B, Hatcher J. Complementary and alterna-tive medicine in pakistan: prospects and limitations. Evidence-Based Compl Altern Med2005; 2:139-142.

2. Boroushaki MT, Sadeghnia HR, Banihashem M, Yavari S. Protective effect of pomegranate seed oil on hexachlorobutadien-induced nephrotoxicity in rats. J Renal Failur 2010; 32:612-617.

3. Ahmad A, Husain A, Mujeeb M, Khan SA, Najmi AK, Siddikue NA, et al. A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pac J Trop Biomed 2013; 3:337-352.

4. Halawani E. Antibactrial activity of Thymoquinone and Thymohydroquinone of Nigella sativa L. and their interaction with some antibiotics. Advan in Biol Res 2009; 3:148-152.

5. Arici M, Sagdic O, Gecgel U. Antibactrial effect of Turkish black cumin (Nigella sativa L.) oils. Grasas y Aceites 2005; 56:259-262.

6. Boskabady NH, Mohsenpur N, Takaloo L. Anti asthmatic effect of Nigella sativa in airways of asthmatic patients. Phytomedicine 2010; 17:707-713.

7. Goreja WG. Black seed: nature`s miracle remedy. New York, NY: Amazing Herbs Press; 2003.

8. Abdel-Sater KA. Gastroprotective effect of Nigella sativa oil on the formation of stress gastritis in hypothyroidal rats. Int J Physiol Pathophysiol Pharmacol 2009; 1:143-149.

9. Yarnell E, Abascal K. Nigella sativa: holy herb of the middle East. Altern Compl Therap 2011; 17: 99-105.

10. Padhye S, Banerjee S, Ahmad A, Mohammad R, Sarkar FH. Fromhere to eternity-the secret of Pharaohs: Therapeutic potential of black cumin seeds and beyond. Cancer Ther 2008; 6:495-510.

11. Abel-Salam BK. Immunomodulatory effects of black seedsand garlic on alloxan-induced diabetes in albino rat. Allergol Immunopathol (Madr) 2012; 40:336-340.

12. Ali BH, Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res 2003; 17:299-305.

13. Shuid AN, Mohamed N, Mohamed IN, Othman F, Suhaimi F, Mohd Ramli ES, et al. Nigella sativa: A potential antiosteoporotic agent. Evid Based Compl Altern Med 2012; 2012:696230.

14. El Mezayen R, El Gazzar M, Nicolls MR, Marecki JC, Dreskin SC, Nomiyama H. Effect of thymoquinone on cyclooxygenase expression and prostaglandin production in a mouse model of allergic airway inflammation. Immunol Lett 2006; 106:72-81.

15. Mahmoud SS, Torchilin VP. Hormetic/cytotoxic effects of Nigella sativa seed alcoholic and aqueous extracts on MCF-7 breast cancer cells alone or in combination with doxorubicin. Cell Biochem Biophys 2013; 66:451-460.

16. Peng L, Liu A, Shen Y, Xu HZ, Yang SZ, Ying XZ, et al. Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol Rep 2013; 29:571-578.

17. Umar S, Zargan J, Umar K, Ahmad S, Katiyar CK, Khan HA. Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. Chem Biol Interact 2012; 197:40-46.

18. Bourgou S, Pichette A, Marzouk B, Legault J. Antioxidant, anti-inflammatory, anticancer and antibacterial activities of extracts from Nigella sativa (black cumin) plant parts. J Food Biochem 2012; 36:539-546.

19. Hosseinzadeh H, Parvardeh S, Asl MN, Sadeghnia HR, Ziaee T. Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus. Phytomedicine2007; 14:621-627.

20. Salama RH. Hypoglycemic effect of lipoic acid, carnitine and Nigella sativa in diabetic rat model. Int J Health Sci (Qassim) 2011; 5:126-134.

21. Abdelmeguid NE, Fakhoury R, Kamal SM, Al Wafai RJ. Effects of Nigella sativa and thymoquinone on biochemical and subcellular changes in pancreatic β-cells of streptozotocin-induced diabetic rats. J Diabetes 2010; 2:256-266.

22. Lei X, Liu M, Yang Z, Ji M, Guo X, Dong W. Thymoquinone Prevents and ameliorates dextran sulfate sodium-induced colitis in mice. Dig Dis Sci 2012; 57:2296-2303.

23. Hosseinzadeh H, Tafaghodi M, Mosavi MJ, Taghiabadi E. Effect of aqueous and ethanolic extracts of Nigella sativa seeds on milk production in rats. J Acupuncture Meridian Stud 2013; 6:18-23.

24. Boskabady MH, Keyhanmanesh R, Saadatloo MA. Relaxant effects of different fractions from Nigella sativa L. on guinea pig tracheal chains and its possible mechanism(s). Indian J Exp Biol2008; 46:805-810.

25. Nazari N. Extraction of pharmacologically active thymoquinone in Nigella sativa L. Doctoral dissertation: Universiti Malaysia Pahang; 2006.

26. El-Tahir K E H, Bakeet DM. The black seed Nigella sativa L. a min for multi cure: a plea for urgent clinical evaluation of its volatile oil. J Taibah Uni Med Sci 2006; 1: 1-19.

27. Hosseinzadeh H, Fazly Bazzaz BS, Haghi MM. Antibacterial activity of total extracts and essential oil of Nigella sativa L. seeds in mice.  Pharmacologyonline2007; 2:429-435.

28. Ziaee T, Moharreri N, Hosseinzadeh H. Review of pharmacological and toxicological effects of Nigella sativa and its active constituents. J Medicinal Plants 2012; 11:16-42. 

29. Hosseinzadeh H, Eskandari M, Ziaee T. Antitussive effect of thymoquinone, a constituent of Nigella sativa seeds, in guinea pigs. Pharmacologyonline 2008; 2:480-484.

30. Muriel P. Roles of free radicals in liver deseases. Hepatol Int 2009; 3:526–536.

31. Tsukamoto H, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 2001; 15:1335-1349.

32. Iimuro Y, Bradford BU, Yamashina S, Rusyn I, Nakagami M, Enomoto N, et al. The glutathione precursor l-2-oxothiazolidine-4-carboxilic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. Hepatology 2000; 31:391-398.

33. Kanter M, Coskun O, Budancamanac M. Hepatoprotective effects of Nigella sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme systems and liver enzymes in carbon tetrachloride-treated rats. World J Gastroenterol 2005; 11:6684-6688.

34. Parola M, Leonarduzzi G, Biasi F, Albano E, Biocca ME, Poli G, et al. Vitamin E dietary supplementation protects against carbon tetrachloride-induced chronic liver damage and cirrhosis. Hepatology1992; 16: 1014-1021.

35. Wu J, Zern MA. Hepatic stellate cells: a target for the treatment of liver fibrosis. J Gastroenterol 2000; 35:665–672.

36. Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 2003; 112:1383–1394.

37. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of platelet-derived growth factor polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 1989; 84:1786–1793.

38. Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K, et al. NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology 2005; 41:1272-1281.

39. Seitz HK, Stickel F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem 2006; 387:349–360.

40. Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci USA 1988; 85:2706–2708.

41. Marx J. Inflammation and cancer: the link grows stronger. Science2004; 36:966–968.

42. de Groot H, Rauen U. Ischemia–reperfusion injury: processes in pathogenetic networks: a review. Transplant Proc 2007; 39:481–484.

43. Jaeschke H. Molecular mechanism of hepatic ischemia–reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003; 284:G15–G26.

44. Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Piña E, Geller DA. Factors in the pathophysiology of the liver ischemia–reperfusion injury. J Surg Res 2008; 147:153–159.

45. Hosseinzadeh H, Moghim FF, Mansouri SMT. Effect of Nigella sativa seed extracts on ischemia-reperfusion in rat skeletal muscle. Pharmacologyonline 2007; 2:326-335.

46. Yesmin F, Rahman Z, Dewan JF, Helali AM, Islam Z, Rahman AM, et al. Hepatoprotective effect of aqueous and N-hexane extract of Nigella sativa in paracetamol (acetaminophen) induced liver disease of rats: a histopathological evaluation. J Pharm 2013; 4:90-94.

47. Abdel-Moneim A, Morsy BM, Mahmoud AM, Abo-Seif MA, Zanaty MI. Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt. EXCLI J 2013; 12: 943-955.

48. Seronello S, Sheikh MY, Choi J. Redox regulation of hepatitis C in nonalcoholic and alcoholic liver. Free Radic Biol Med 2007; 43:869–882.

49. Melhem A, Stern M, Shibolet O, Israeli E, Ackerman Z, Pappo O, et al. Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. J Clin Gastroenterol 2005; 39:737–742.

50. Al-Okbi SY, Mohamed DA, Hamed TE, Edris AE. Potential protective effect of Nigella sativa crude oils towards fatty liver in rats. Eur J Lipid Sci Technol 2013; 115:774–782.

51. Danladi J, Abdusalam A, Timbuak JA, Miriga AA, Dahiru AU. Hepatoprotective effect of black seed (Nigella sativa) oil on carbon tetrachloride (ccl4) induced liver toxicity in adult wistar rats. J Dental Med Sci 2013; 4:56-62.

52. Zafeer MF, Waseem M, Chaudhari S, Parvez s. Cadmium-Induced hepatotoxicity and its abrogation by thymoquinone.  J Bio Mole Toxico 2012; 26:199-205.

53. Nehar S, Kumari M. Ameliorating effect of Nigella sativa oil on Thioacetamide-induced liver cirrohsis in albino rats. Ind J Pharm Edu Res 2013; 47:135-139.

54. Salem ML. Immunomodulatory and therapeutic effects of Nigella sativa L. seed. Int Immunopharmacol2005; 5:1749-1770.

55. Calvino J, Lens XM, Romero R, Sanchez Guisande D. Long-term anti-proteinuric effect of Losartan in renal transplant recipients treated for hypertension. Nephrol Dial Transplant 2000; 15: 82-86.

56. Aboul-Ela EI. Cytogenetic studies on Nigella sativa seeds extract and thymoquinone on mouse cells infected with schistosomiasis using karyotyping. Mutat Res 2002; 516:11-17.

57. Al Rowais NA. Herbal medicine in the treatment of diabetes mellitus. Saudi Med J 2002; 23:1327-1331.

58. Kalus U, Pruss A, Bystron J, Jurecka M, Smekalova A, Lichius JJ, et al. Effect of Nigella sativa (black seed) on subjective feeling in patients with allergic diseases. Phytother Res 2003; 17:1209-1214.

59. Nagi MN, Mansour MA. Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity in rats: a possible mechanism of protection. Pharmacol Res 2000; 41:283-289.

60. Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol 2003; 26: 87-98.

61. Mohamed A, Afridi DM, Garani O, Tucci M. Thymoquinone inhibites the activation of NF-kappaB in the bain and spinal cord of experimental autoimmune encephalomyelitis. Biomed Sci Instrum 2005; 41:388-393.

62. El-Tawil O, Moussa SZ. Antioxidant and hepatoprotective effects of thymoquinone against carbon tetrachloride-induced hepatotoxicity in isolated rat hepatocyte. J Egypt Soc Toxicol 2006; 34:33-41.

63. Burits M, Bucar F. Antioxidant activity of Nigella sativa essential oil. Phytother Res 2000; 14:323-328.

64. Fouda AMM, Daba MHY, Yousef Ahmed AR. Antigenotoxic effects of thymoquinone against benzo[a]pyrene and mitomycin C -induced genotoxicity in cultured human lymphocytes. Research in Immunology: An International Journal 2014; 2014: Articl ID 5352.79.

65. Mahmoud MR, El-Abhar HS, Saleh S. The effect of Nigella sati_a oil against the liver damage induced by Schistosoma mansoni infection in mice. J Ethnopharmacol 2002; 79:1-11.

66. Yildiz F, Coban S, Terzi A, Ates M, Aksoy N, Cakir H, et al. Nigella sativa relieves the deleterious effects of ischemia reperfusion injury on liver. World J Gastroenterol2008; 14:5204-5209.

67. Awad A, Kamel R, Elsayed Sherief MA. Effect of thymoquinone on hepatorenal dysfunction and alteration of CYP3A1 and spermidine/spermine N-1-acetyl-transferase gene expression induced by renal ischaemia–reperfusion in rats. J Pharm Pharmacol 2011; 63:1037-42. 

68. Sayed-Ahmed MM, Aleisa AM, Al-Rejaie SS, Al-Yahya AA, Al-Shabanah OA, Hafez MM, et al. Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. Oxid Med Cell Longev 2010; 3:254-261.

69. Daba MH, Abdel-Rahman MS. Hepatoprotective activity of thymoquinone in isolated rat hepatocytes. Toxicol Lett 1998; 95:23-29.

70. Khalife KH, Lupidi G. Nonenzymatic reduction of thymoquinone in physiological conditions. Free Radic Res 2007; 41:153-161.

71. Mansour M, Tornhamre S. Inhibition of 5 lipoxygenase and leukotriene C4 synthase in human blood cells by thymoquinone. J Enzyme Inhib Med Chem 2004; 19:431-436.

72. Mahgoub AA. Thymoquinone protects against experimental colitis in rats. Toxicol Lett 2003; 143:133-143.

73. Tekeoglu I, Dogan A, Ediz L, Budancamanak M, Demirel A. Effects of thymoquinone (volatile oil of black cumin) on rheumatoid arthritis in rat models. Phytother Res 2007; 21:895-897.

74. Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B. N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats. Med Sci Monit2006; 12:BR274-BR278.

75. Badary OA, Bdel-Naim AB, Bdel-Wahab MH, Hamada FM. The influence of thymoquinone on doxorubicine-induced hyperlipidemic nephropathy in rats. Toxicology 2000; 143:219-226.

76. Zubair H, Khan HY, Sohail A, Azim S, Ullah MF, Ahmad A, et al. Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants. Cell Death Dis 2013; 4:e660. 

77. Racoma IO, Meisen WH, Wang QE, Kaur B, Wani AA. Thymoquinone Inhibits Autophagy and Induces Cathepsin-Mediated, Caspase-Independent Cell Death in Glioblastoma Cells. PLoS ONE 2013; 8: e72882.

78. Dollah MA, Parhizkar S, Latifi LA, Binhasan MH. Toxicity effect of Nigella sativa on the liver functions of rats.  Adv Pharm Bull 2013; 3:97-102.

79. Ashraf SS, Rao MV, Kaneez FS, Qadri S, Al-Marzouqi AH, Chandranath IS, et al. Nigella sativa Extract as a Potent Antioxidant for Petrochemical-
Induced Oxidative Stress. J Chromatogr Sci 2011; 49:321-326.

80. Shuddek GM. Protective roles of thymoquinone against liver damage induced by tamoxifen in female rats. Can J Physiol Pharmacol 2014; 92:640-644.

81. Hagag AA, Abd Elal AM, Elsheik A, Elzamarany EA. Protective Effect of Nigella sativa Oil against Methotrexate Induced Hepatotoxicity in Children with Acute Lymphoblastic Leukemia. J Leuk 2013; 1:1-7.