Heracleum persicum extract improves cyclophosphamide-induced liver toxicity and oxidative stress in male rats

Document Type: Original Article




Background and aims: Cyclophosphamide (CP), is a widely used cytotoxic alkylating agent with antitumor and immunosuppressant properties. In spite of its therapeutic importance, a wide range of adverse effects including reproductive toxicity have been demonstrated following cp treatment in humans and experimental animals.The current report was designed to investigate the possible protective effect of Heracleumpersicum against cyclophosphamide(CP)-induced hepatotoxicity in rats.
Methods: In this experimental research 30 male albino Wistar rats, with body weights of 180-200 g were obtained. The animals were randomly assigned into five groups of 6 in each.Group 1 (control) group 2 (only receiving cyclophosphamide) and groups 3, 4, 5 (receiving cyclophosphamide with differentdoses ofmethanol extract of H.persicum). In order to induce liver toxicity in groups 2, 3, 4 and 5, CP was administered as a single dose (0.5 mg/kg), intraperitoneally and methanol extracts (0.5, 1 and 2 mg/Kg) wereadministered by gavage in 24-h cycles over a 21-day period.
Results: The results showed that administration of CP induced hepatic damage associated with significant increase in the serum marker enzymes aspartate and alanine transaminases (AST, ALT) and alkaline phosphatase (ALP) level in the CP treated group in comparison with the control (p<0.05). In addition, it was revealed that CP-administration cause a significant decrease (p<0.05) in activity of catalase (CAT) and superoxide dismutase (SOD). However, groups which received the extract of H. persicum in association with CP represented significantly improved parameters.
Conclusion: The results revealed that the methanol extract of H. pesicum has hepatoprotective effect against cyclophosphamide(CP)-induced toxicity in rats.


Main Subjects

1. Mroueh, M. Saab, Y. Rizkallah, R.:Hepatoprotective activity of Centauriumerythraea on acetaminophen-induced hepatotoxicity in rats. Phytother. Res.,2004;18, 431–433.

2. Shalizar Jalali, A. Hassanzadeh, Sh. Malekinejad, H., Chemoprotective effect of Crataegus monogyna aqueous extract against cyclophosphamide- induced reproductive toxicity. Veterinary Research Forum 2011; 2 (4) 266- 273.

3. Ludeman SM. The chemistry of the metabolites of cyclophosphamide.Curr Pharm Des., 1999; 5: 627–643

4. Kern, JC.Kehrer,JP.:Acroleininduced cell death: a caspase influenced decision between apoptosis and oncosis/necrosis. ChemBiol Interact., 2002; 139: 79– 95.

5. Anderson, D. Bishop, JB. Garner, RC. et al. Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks. Mutat Res., 1995; 330: 115– 181.

6. Fulya, U., Feraye, E., Atila, A., Protective effect of Salvia offi cinalis extract against cyclophosphamide-induced genotoxicity and oxidative stress in rats. Turk. J. vet. Anim 2012; 36(6): 646-654.

7. Kopecna, L.: Late effects of anticancer therapy on kidney function in children with acute lymphoblastic leukemia Bratisl. Lek.Listy., 2001; 102: 357–360.

8. Gustafsson, L.L. Eriksson, L.S. Dahl, M.L. Eleborg, L. Ericzon, B.G. Nyberg, A.: Cyclophosphamide-induced acute liver failure requiring transplantation in a patient with genetically deficientdebrisoquine metabolism: a causal relationship? J. Intern. Med., 1996; 240: 311– 314.

9. Madle, E. Korte, A. Beek, B.: Species diff erences in mutagenicity testing. II. Sisterchromatid exchange and micronucleus induction in rats, mice and Chinese hamsters treated with cyclophosphamide. Mutagenesis., 1986; 1: 419–422.

10. Giesy, J.P., Kong, Z., Cui, Y. Protective effects of eicosapentaenoic acid on genotoxicity and oxidative stress of cyclophosphamide in mice. Environ. Toxicol 2011; 26: 217– 223.

11. Todorova, V. Vanderpool, D. Blossom, S. Nwokedi, E. Hennings, L. Mrak, R.Klimberg, V.S.: Oral glutamine protects against cyclophosphamide-induced cardiotoxicity in experimental rats through increase of cardiac glutathione. Nutrition., 2009; 25: 812–817.

12. Grzegorczyk, I. Matkowski, A. Wysokinska, H.: Antioxidant activity of extracts from in vitro cultures of Salvia officinalis L. Food Chem., 2007; 104: 536–541.

13. Weisburger, J.H.: Antimutagenesis and anticarcinogenesis from the past to the future. Mutat. Res., 2001; 480-481: 23–35.

14. Pimenov, M. G. &Leonov, M. V.: The Asian Umbelliferae biodiversity database (ASIUM) with particular reference to SouthWest Asian Taxa. Turkish Journal of Botany.,2004;28, 139–145.

15. Firuzi, o. Asadollahi, M. Gholami, M. Javidnia, K. Composition and biological activities of essential oils from four Heracleum specie. Food Chemistry 2010; 122: 117–122.

16. Amin, G., Popular medicinal plants of Iran. Tehran: Tehran University of Medical Sciences Press 2008; 42:396-399.

17. Ghodsi, B.: Flavonoids of three Heracleum species: H. Persicum L, H. sphondylium L. and H. montanum. Bull. TravSoc Pharm Lyon., 1976; 20: 3-8.

18. Souri, F.Farsam, H.Sarkheil, P.Ebadi,F.: Antioxidant activity of some furanocoumarins isolated from Heracleumpersicum. Pharm Biol., 2004; 42: 396-399.

19. Dehghan, G.Shafiee, A.Ghahremani, M.Ardestani, S.Abdollahi,M.: Antioxidant potential of various extracts from Ferula szovitsiana in relation to their phenolic contents. Pharm Biol., 2007; Vol. 45: No. 9, pp. 1– 9.

20. Diana Anderson ap JBBb, R. Colin Garner, Patricia OstroskyWegman d., Selby PB.; Cyclophosphamide: Review of its mutagenicity for an assessment of potential germ cell risks. Mutation Research 1995; 330: 115-181.

21. Shahrani M, nabavizadeh F, Shirzad H, yousefi H, Moradi M T, Moghadasi J. effect of Heracleum persicum extract on acid and pepsin secretion level in both basic and stimulated conditions with pentagastrin in rat. J Shahrekord univ Med Sci. 2006; 7 (4) : 35-41.

22. bi, H.: Catalase in vitro. Methods Enzymol., 1984; 105: 121–126.

23. Winterbourn, C. Hawkins, R. Brian, M.Carrell, R.: The estimation of red cell superoxide dismutase activity. J Lab Clin Med., 1975; 85: 337.

24. McDiarmid, MA.Iype, PT.Koldner, K.Jacobnson, KD. Strickland, PT.: Evidence for acrolein-modified DNA in peripheral blood leucocytes of cancer patients treated with cyclophosphamide.,1991.

25. Lahouel, M.Fillastre,JP.:Role of flavonoids in the prevention of haematoxicity due to chemotherapeutic agents. Haema.,2004;7:313–320.

26. Patel, J.M. Block, E.R.: Cyclophosphamide-induced depression of the antioxidant defense mechanisms of the lung. Exp. Lung Res., 1985; 8: 153–165.

27. Kumar, G.Banu, SG.Kannan, V.Pandian,RM.: Antihepatotoxic effect of β-carotene on paracetamol induced hepatic damage in rats. Ind J Exp Biol., 2005; 43:351–355

28. Searle, AJ. Wilson, RL.:Glutathione peroxidase: effect of superoxide, hydroxyl and bromine free radicals on enzymicactivity. Int J Radi Biol., 1980; 37: 213.

29. Mahmoud, AM. Hussein, OE. Ramadan, SA.Amelioration of cyclophosphamide-induced hepatotoxicity by the brown seaweed Turbenariaornata.Int J ClinToxicol.,2013;1:9–17 Mutat Res 248:93–99.

30. Rajasekaran, N.S. Devaraj, H.Devaraj, S.N.: The effect of glutathione monoester (GME) on glutathione (GSH) depleted rat liver. J NutrBiochem., 2002; 13:302-306.

31. Tripathi, D.N. Jena, G.B.: Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: a study in mice. ChemBiol Interact., 2009; 180: 398-406.

32. Atefeh, H.Mahnaz, A. and S, Abdolhamid, A.: Medicinal Effect of Heracleumpercicum (Golpar). Middle-EastJournal of Scientific Research., 2010; 5 (3): 174-176.

33. Oboh, G.Akomolafe, LT.Adefegha, AT.Adetuyi, OA. Inhibition of cyclophosphamide induced oxidative stress in rat brain by polar and non-polar extracts of Annatto (Bixaorellana) seeds. ExpToxicolPathol., 2011;63:257– 62.

34. Abe, K. Saito, H. Effect of Saffron extract and its constituent crocin on learning behavior and long-term potentiation.Phytotherapy Research.,2000; 14(3): 149-152.