Aqueous extract of walnut (Juglans regia L.) protects mice against cyclophosphamideinduced biochemical toxicity

Abstract

Walnut (Juglans regia L.) is extensively used in traditional systems of medicine for treatment of various ailments. It is described as an anticancer, tonic, blood purifier and detoxifier agent. The present study was undertaken to investigate modulatory effects of walnut extract on the toxicity of an anticancer drug, cyclophosphamide (CP) with special reference to protection against disruption of drug metabolizing and antioxidant enzymes. Plant extract+CP group animals showed restoration in the level of cytochrome P450 (CYP) content and in the activities of glutathione S-transferase (GST), glutathione peroxidase (GP) and catalase (CAT) in both liver and kidneys. But plant extract restored the activity of super oxide dismutase (SOD) and the level of reduced glutathione (GSH) in the kidneys only when compared with CP-treated animals. Plant extract treatment alone caused significant reduction in the content of CYP in the kidneys mainly. The extract showed a significant increase in the level of GSH and in the activities of GP in both the tissues and CAT in liver only, whereas no significant change was observed in the activities of GST and SOD. CP treatment resulted in a significant (P<0.01) increase in the lipid peroxidation (LPO) in the liver and kidneys compared with controls, while the extract CP treated group showed a significant decrease in the LPO in liver and kidneys when compared with the CP-treated group. The study shows that the use of J. regia extract might be helpful in abrogation of CP toxicity during the chemotherapy.

Keywords

antioxidant enzymes biochemical toxicity cyclophosphamide Juglans regia oxidative stress protection

References

Fleming RE . An overview of cyclophosphamide and ifosmaide pharmacology . Pharmacotherapy 1997; 17: 1465-1545 .

Baumann F , Preiss R . Cyclophosphamide and related anticancer drugs . J Chromatogr B Biomed Sci Appl 2001; 764: 173-192

Mirkes PE . Cyclophosphamide teratogenesis.A review . Teratogen Carcinogen Mutagen 1985; 5: 75-88 .

Patel JM . Stimulation of cyclophosphamide-induced pulmonary microsomal lipid peroxidation by oxygen . Toxicology 1987; 45: 79-91 .

Sulkowska M , Sulkowski S , Skrzydlewska E , Farbiszewski R . Cyclophosphamide-induced generation of reactive oxygen species. Comparison with morphological changes in type II alveolar epithelial cells and lung capillaries . Exp Toxicol Pathol 1998; 50: 209-220 .

Boddy AV , Yule SM . Metabolism and pharmacokinetics of oxazaphosphorines . Clin Pharmacokin 2000; 38: 291-304 .

Kaya H , Oral B , Ozguner F , Tahan V , Babar Y , Delibas N . The effect of melatonin application on lipid peroxidation during cyclophosphamide therapy in female rats . Zentral Gynakal 1999; 121: 499-502 .

Rekha PS , Kuttan G , Kuttan R . Effect of Brahma Rasayana on antioxidant systems and cytokine levels in mice during cyclophosphamide administration . J Exp Clin Cancer Res 2001; 20: 219-223 .

Dohadwala M , Ray PK . In vivo protection by protein A of hepatic microsomal mixed function oxygenase system of cyclophosphamide-treated rats . Cancer Che-mother Pharmacol 1985; 14, 135-138 .

10.

Ray PK , Dohadwala M , Bandyopadyay SK Canchanapan P , McLaughlin D . Rescue of rats from large dose cyclophosphamide toxicity using protein A . Cancer Chemother Pharmacol 1985; 14: 59-62 .

11.

Venkatesan N , Chandrakasan G . Modulation of cyclophosphamide-induced early lung injury by curcumin, an anti-inflamtory antioxidant . Molec Cell Biochem 1995; 142: 79-87 .

12.

Brock N . The development of mesna for the inhibition of urotoxic side effects of cyclophosphamide, ifosfamide and other oxazaphosphorine cytostatics . Rec Res Cancer Res 1980; 74: 270-278 .

13.

Habs M , Hebebrand J , Schmahl D . Influence of sulfur containing compounds on the acute toxicity of cyclophosphamide in male Sprague-Dawley rats . Arzneimittel-Forsch 1984; 34: 792-793 .

14.

Mathew S , Kuttan G . Antioxidant activity of Tinospora cardiofolia and its usefulness in the amelioration of cyclophosphamide induced toxicity . J Exp Clin Cancer Res 1997; 16: 407-411 .

15.

Ziauddin M , Phansalkar N , Patki PS , Diwanay S , Patwardhan B . Studies on the immunomodulatory effects of Ashwagandha . J Ethnopharmacol 1996; 50: 69-76 .

16.

Sharma N , Trikha P , Athar M , Raisuddin S . Inhibitory effect of Emblica officinalis on the in vivo clastogeni city of benzo[a]pyrene and cyclophosphamide in mice . Human Exp Toxicol 2000; 19: 377-384 .

17.

Bin-Hafeez B , Ahmad I , Haque R , Raisuddin S . Protective effect of Cassia occidentalis L. on cyclophosphamide-induced suppression of humoral immunity in mice . J Ethnopharmacolol 2001; 75: 13-18 .

18.

Haque R , Bin-Hafeez B , Ahmad I , Parvez S , Pandey S , Raisuddin S . Protective effects of Emblica officinalis Gaertn. in cyclophosphamide-treated mice . Human Exp Toxicol 2001; 20: 643-650 .

19.

Brown D . Encyclopaedia of herbs and their uses. London: Dorling Kindersley , 1995.

20.

Yeung-Him-Che . Handbook of Chinese herbs and formulas. Los Angeles: Institute of Chinese Medicine , 1985.

21.

Kirtikar KR , Basu BD . Indian medicinal plants. Dehradun: International Book Distributors , 1975.

22.

Kaur K , Michael H , Arora S , Harkonen PL , Kumar S . Studies on correlation of antimutagneic and antiproliferative activities of Juglans regia L . J Environ Pathol Toxicol Oncol 2003; 22: 59-67 .

23.

Sharma N , Trikha P , Athar M , Raisuddin S . Protective effect of Cassia occidentalis extract on chemicallyinduced chromosomal aberrations in mice . Drug Chem Toxicol 1999; 22: 643-653 .

24.

Sharma N , Trikha P , Athar M , Raisuddin S . In vitro inhibition of carcinogen-induced mutagenicity by Cassia occidentalis and Emblica officinalis . Drug Chem Toxicol 2000; 23: 477-484 .

25.

Omura T , Sato R . The carbon monoxide-binding pigment of liver microsomes, I. Evidence for its hemoprotein nature . J Biol Chem 1964; 239: 2370-2378 .

26.

Jollow, DJ , Mitchell, JR , Zampaglione, N , Gillete, JR Bromobenzene induced liver necrosis: protective role of glutathione and evidence for 3,4-bromobenzeneox ide as the hepatotoxic metabolite . Pharmacology 1974; 11: 151-169 .

27.

Habig WH , Pabst MJ , Jakoby WB . Glutathione S-transferase. The first enzymatic step in mercapturic acid formation . J Biol Chem 1974; 249: 7130-7139 .

28.

Claiborne A . Catalase activity. In Greenwald RA ed. CRC handbook of methods in oxygen radical research. Boca Raton: CRC Press , 1985; 283-284.

29.

Mohandas J , Marshall JJ , Duggins GG , Horvath JS , Tiller D . Differential distribution of glutathione and glutathione related enzymes in rabbit kidneys. Possible implications in analgesic nephropathy . Biochem Pharmacol 1984; 33: 1801-1807 .

30.

Utley HG , Bernheim F , Hochstein P . Effect of sulfhydryl reagent on peroxidation of microsomes . Arch Biochem Biophys 1967; 118: 29-32 .

31.

Lowry OH , Rosenbrough NJ , Farr AL , Randall RJ . Protein measurement with Folin phenol reagent . J Biol Chem 1951; 193: 265-275 .

32.

Gurtoo HL , Marinello AJ , Struck RF , Paul B , Dahms RP . Studies on the mechanism of denaturation of cytochrome P450 by cyclophosphamide and its metabolites . J Biol Chem 1981; 256: 11691-11701 .

33.

Sheweita SA , Newairy AA , Mansour HA , Yousef MI . Effect of some hypoglycemic herbs on the activity of phase I and II drug-metabolizing enzymes in alloxaninduced diabetic rats . Toxicology 2002; 174: 131-139 .

34.

Gomes-Carneiro MR , De-Oliveira AC , De-Carvalho RR , Araujo IB , Souza CA , Kuriyama SN , Paumgartten FJ . Inhibition of cyclophosphamide-induced teratogenesis by beta-ionone . Toxicol Lett 2003; 138: 205-213 .

35.

Goud VK , Polasa K , Krishnaswamy K . Effect of turmeric on xenobiotic metabolising enzymes . Plant Foods Human Nutr 1993; 44: 87-92 .

36.

Thapliyal R , Deshpande SS , Maru GB . Mechanism(s) of turmeric mediated protective effects against benzo(a)pyrene-derived DNA adducts . Cancer Lett 2002; 175: 79-88 .

37.

Singh RP , Banerjee S , Rao AR . Effect of Aegle marmelos on biotransformation enzyme systems and protection against free radical mediated damage in mice . J Pharm Pharmacol 2000; 52: 991-1000 .

38.

Singh RP , Dhanalakshmi S Rao AR . Chemomodulatory action of Aloe vera on the profiles of enzymes associated with carcinogen metabolism and antioxidant status regulation in mice . Phytomedicine 2000; 7: 209-219 .

39.

Hartman PE , Shankel DM . Antimutagens and anticarcinogens: a survey of putative intercepter molecules . Environ Mole Mutagen 1990; 15: 145-182 .

40.

Ketterer B . Glutathione S-transferase and prevention of cellular free radical damage . Free Rad Res 1998; 28: 647-658 .

41.

De Flora S . Mechanisms of inhibitors of mutagenesis and carcinogenesis . Mutat Res 1998; 402: 151-158 .

42.

Reed DJ . Glutathione: toxicological implications . Ann Rev Pharmacol Toxicol 1990; 30: 603-631 .

43.

Gaetani GF , Galiano S , Canepa L , Ferraris AM , Kirkman HN . Catalase and glutathione peroxidases are equally effective in detoxification in human erythrocytes . Blood 1989; 73: 334-339 .

44.

Cooper JA Jr , Merrill WW , Reynolds HY . Cyclophosphamide modulation of bronchoalveolar cellular populations and macrophage oxidative metabolism: Possible mechanisms of pulmonary pharmacotoxicity . Am Rev Respir Dis 1986; 134: 108-198 .

45.

Biaglow JE , Varnes ME , Epp ER , Clark EP . Antioxidant and redox enzymes in radioprotection . Pharmacol Therap 1988; 39: 275-286 .

46.

Bhanumathi P , Devi PU . Modulation of glutathione depletion and lipid peroxidation by WR-77913 a 2mercaptopropionylglycine in cyclophosphamide chemotherapy . Ind J Exp Biol 1994; 32: 562-564 .

47.

Anderson KJ , Teuber SS , Gobeille A , Cremin P , Waterhouse AL , Steinberg FM . Walnut polyphenolics inhibit in vitro human plasma and LDL oxidation . J Nutr 2001; 131: 2837-2842 .

48.

Ohsugi M , Fan W , Hase K , Xiong Q , Tezuka Y , Komatsu K , Namba T , Saitoh T , Tazawa K , Kadota S . Activeoxygen scavenging activity of traditional nourishingtonic herbal medicines and active constituents of Rhodiola sacra . J Ethnopharmacol 1999; 67: 111-119 .

49.

Halvorsen BL , Holte K , Myhrstad MC , Barikmo I , Hvattum E , Remberg SF , Wold AB , Haffner K , Baugerod H , Andersen LF , Moskaug O , Jacobs DR Jr , Blomhoff R . A systematic screening of total antioxidants in dietary plants . J Nutr 2002; 132: 461-471

50.

ÇagQlarirmak N . Biochemical and physical properties of some walnut genotypes (Juglans regia L.) . Nahrung-Food 2003; 47: 28-32 .

51.

Sahu CS , Green S . Food antioxidants: their dual role in carcinogenesis. In Baskin IS , Salem H eds. Oxidants, antioxidants, and free radicals. London: Taylor & Francis , 1997; 207-226.