A study of the effect of Nigella sativa (black seeds) on methotrexate-induced hepatotoxicity in rabbits
Keywords:
Methotrexate, Liver toxicity, Antioxidant, Nigella sativaAbstract
Background: To evaluate the effectiveness of Nigella sativa (NS) in the prevention of hepatotoxicity of large doses of methotrexate (MTX) (IP) in rabbits.
Methods: Three groups of male rabbits, six in each were used. Oral dosing was administered as a paste; formula 1 was prepared by mixing 2 g flour with water; formula 2 contained flour and NS and water. Group 1 was fed with formula 1 daily and injected with 2 ml/kg normal saline IP. Group 2 was given formula 1 daily with 20 mg/kg MTX IP. Group 3 was fed with formula 2 daily + MTX 20 mg/kg IP. Injections were given weekly for 5 weeks, and then the animals were sacrificed at day 39. Liver enzymes, malondialdehyde (MDA), glutathione (GSH), and histopathology of the liver were evaluated.
Results: Liver enzymes, serum, and liver MDA were significantly increased by MTX. MTX + NS treatment significantly reduced the rise in liver enzymes, MDA in serum with little effect on liver MDA. Serum aspartate aminotransferase, alkaline phosphatase, and bilirubin were reduced from 82.8±18.04 U/L, 4.9±2.0 kind and king unit/100 ml and 0.74±0.1 mg/dl to 56.1±7.5, 2.0±0.6 and 0.27±0.1 respectively. Unexpectedly, serum and liver GSH were slightly increased by MTX. Treatment with MTX + NS further increased these levels. Histologically, portal and lobular sinusoidal dilatation, lymphocytic infiltration, and hepatocyte hydropic degeneration were seen in all rabbits on MTX, which disappeared in three rabbits on NS + MTX.
Conclusion: NS is hepatoprotective against MTX induced hepatotoxicity.
References
Smith SW, Nelson LS. Case files of the New York City Poison Control Center: antidotal strategies for the management of methotrexate toxicity. J Med Toxicol. 2008;4(2):132-40.
Ng LC, Lee YY, Lee CK, Wong SM. A retrospective review of methotrexate-induced hepatotoxicity among patients with psoriasis in a tertiary dermatology center in Malaysia. Int J Dermatol. 2013;52(1):102-5.
Strober BE. Methotrexate and cyclosporine in psoriasis revisited. Semin Cutan Med Surg. 2014;33(2 Suppl 2):S27 30.
Gilani ST, Khan DA, Khan FA, Ahmed M. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. J Coll Physicians Surg Pak. 2012;22(2):101-4.
Weinblatt ME. Methotrexate in rheumatoid arthritis: a quarter century of development. Trans Am Clin Climatol Assoc. 2013;124:16-25.
Hassan AS, Ahmed JH, Al-Haroon SS. A study of the effect of Nigella sativa (Black seeds) in isoniazid (INH)-induced hepatotoxicity in rabbits. Indian J Pharmacol. 2012;44(6):678-82.
El-Sayed WM. Upregulation of chemoprotective enzymes and glutathione by Nigella sativa (black seed) and thymoquinone in CCl4-intoxicated rats. Int J Toxicol. 2011;30(6):707-14.
Ahmed JH, Ibraheem AY, Al-Hamdi KI. Evaluation of the efficacy, safety and antioxidant effect of Nigella sativa in patients with psoriasis: a randomized clinical trial. J Clin Exp Invest. 2014;5:186-93.
Dwarampudi LP, Palaniswamy D, Nithyanantham M, Raghu PS. Antipsoriatic activity and cytotoxicity of ethanolic extract of Nigella sativa seeds. Pharmacogn Mag. 2012;8(32):268-72.
Gad SC. Animal Models in Toxicology. 2nd Edition. New York: CRC, Taylor & Francis; 2007: 60-1.
Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302-10.
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8.
Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriatics. Acta Pathol Microbiol Scand A. 1977;85(4):511-8.
Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;5:CD000951.
Zubairi MB, Ahmed JH, Al-Haroon SS. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits. Indian J Pharmacol. 2014;46(6):644-8.
Al-Saleh E, Al-Harmi J, Nandakumaran M, Al-Shammari M, Al-Jassar W. Effect of methotrexate administration on status of some essential trace elements and antioxidant enzymes in pregnant rats in late gestation. Gynecol Endocrinol. 2009;25(12):816-22.
Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2):163-72.
Kulkarni KS, Rafiq MD, Gopumadhavan S, Venkataranganna MV, Madhumathi BG, Mitra SK. Protective effect of Liv.52 on Na+-K+-ATPase activity in paracetamol-induced hepatotoxicity. Med Update. 2002;5:53-6.
Mahmmoud YA, Christensen SB. Oleic and linoleic acids are active principles in Nigella sativa and stabilize an E(2)P conformation of the Na,K-ATPase. Fatty acids differentially regulate cardiac glycoside interaction with the pump. Biochim Biophys Acta. 2011;1808(10):2413-20.
Ezz HS, Khadrawy YA, Noor NA. The neuroprotective effect of curcumin and Nigella sativa oil against oxidative stress in the pilocarpine model of epilepsy: a comparison with valproate. Neurochem Res. 2011;36(11):2195-204.
