Investigation of the effect of watercress via nuclear factor-E2-related factor-2 pathway on 7,12-dimethylbenz[a]anthracene-induced oxidative damage in rat liver

Abstract

Aim: Nuclear factor E2-related factor-2 (Nrf2) regulates many cytoprotective antioxidants, and detoxifying enzymes, has been a hopeful approach for chemoprevention of cancer. We researched the chemopreventive impact of watercress on the DMBA-induced oxidative damage in the rat liver via the Nrf2/ARE signalling pathway in the present study. Material and Method: Female Wistar albino rats have categorized into three groups. The control was the first group, rats in the second and third groups were administered 7,12-dimethylbenz[a]anthracene (DMBA) (20 mg/kg b.w., i.p.) and rats in the third group were given daily doses of watercress (250 mg/kg b.w. Nasturtium officinale R.Br. for 4 weeks by oral gavage). Antioxidant and phase II detoxification enzyme activities, Nrf2 transcription factor level in liver, and serum ALT were determined. Also, histopathological analysis of the liver was performed. Results: We observed that watercress induces DNA-binding of Nrf2. It was related to increased enzyme activities of phase II detoxifying and the antioxidant. Our results also demonstrated that watercress ameliorated liver injury. Conclusion: Our data ensured considerable evidence that the dietary watercress ameliorates DMBA induced liver toxicity via regulating the activation of the Nrf2/ARE pathway which increases the expression of cytoprotective enzymes.

Keywords

• Watercress
• Nrf2
• DMBA
• Xenobiotic enzymes
• Hepatoprotective effect

Supporting Institution

The Scientific Research Projects Unit of İnönü University

Project Number

Grant/Award Number: 2015/84

References

1. Rengarajan T, Nandakumar N, Balasubramanian MP. D-Pinitol prevents rat breast carcinogenesis induced by 7,12-Dimethylbenz[a]anthracene through inhibition of Bcl-2 and induction of p53, caspase-3 proteins and modulation of hepatic biotransformation enzymes and antioxidants. Biomed Prev Nutr 2013; 3: 31-41.
2. Shimada T. Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug Metab Pharmacokinet 2006; 21: 257-76.
3. Xue W, Warshawsky D. Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. Toxicol Appl Pharmacol 2005; 206: 73-93.
4. Gelboin HV. Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation of mixed-function oxidases and related enzymes. Physiol Rev 1980; 60: 1107-66.
5. Bharali R, Tabassum J, Azad MRH. Chemomodulatory effect of moringa oleifera, lam, on hepatic carcinogen metabolising enzymes, antioxidant parameters and skin papillomagenesis in mice. Asian Pac J Cancer Prev 2003; 4: 131-9.
6. Manzanares MÁ, Solanas M, Moral R, Escrich R, Vela E, Escrich E. Ontogeny of the major xenobiotic-metabolizing enzymes expression and the dietary lipids modulatory effect in the rat dimethylbenz(a)anthracene-induced breast cancer model. J Biochem Mol Toxicol 2014; 28: 539-48.
7. Li Y, Paonessa JD, Zhang, Y. Mechanism of chemical activation of Nrf2. PLoS ONE 2012; 7: e35122.
8. Baird L, Dinkova-Kostova AT. The cytoprotective role of the Keap1–Nrf2 pathway. Arch Toxicol 2011; 85: 241-72.

9. Klimek-Szczykutowicz M, Szopa A, Ekiert H. Chemical composition, traditional and professional use in medicine, application in environmental protection, position in food and cosmetics industries, and biotechnological studies of Nasturtium officinale (watercress) – a review. Fitoterapia 2018; 129: 283-92.
10. Ribeiro Rde A, de Barros F, de Melo MM, et al. Acute diuretic effects in conscious rats produced by some medicinal plants used in the state of São Paulo, Brasil. J Ethnopharmacol 1988; 24: 19-29.
11. Yaricsha CA, Rissyelly K. ACE inhibitory activity, Total phenolic and flavonoid content of watercress (Nasturtium officinale R. Br.) extract. Pharm J 2017; 9: 249-51.
12. Hoseini HF, Gohari AR, Saeidnia S, Majd NS, Hadjiakhoondi A. The effect of Nasturtium officinale on blood glucose level in diabetic rats. Pharmacol Ther 2009; 3: 866–71.
13. Bahramikia S, Yazdanparast R. Effect of hydroalcoholic extracts of Nasturtium officinale leaves on lipid profile in high-fat diet rats. J Ethnopharmacol 2008; 115: 116-21.
14. Camacho-Corona Mdel R, Ramírez-Cabrera MA, Santiago OG, Garza-González E, Palacios P, IdeLuna-Herrera J. Activity against drug resistant-tuberculosis strains of plants used in Mexican traditional medicine to treat tuberculosis and other respiratory diseases. Phytother Res 2008; 22: 82-5.
15. Boyd LA, McCann MJ, Hashim Y, Bennett RN, Gill CI, Rowland IR. Assessment of the anti-genotoxic, anti-proliferative, and anti-metastatic potential of crude watercress extract in human colon cancer cells. Nutr Cancer 2006; 55: 232-41.
16. Giallourou N, Oruna-Concha MJ, Harbourne N. Effects of domestic processing methods on the phytochemical content of watercress (Nasturtium officinale). Food Chem 2016; 212: 411-9.
17. Talalay P, Fahey JW. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr 2001; 131: 3027-33.
18. Keum YS, Owuor ED, Kim BR, Hu R, Kong ANT. Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC). Pharm Res 2003; 20: 1351-55.
19. Saarinen NM, Warri A, Airio M, Smeds A, Makela S. Role of dietary lignans in the reduction of breast cancer risk. Mol Nutr Food Res 2007; 51: 857-66.
20. Jiao D, Yu MC, Hankin JH, Low S-H, Chung F-L. Total isothiocyanate contents in cooked vegetables frequently consumed in Singapore. J Agric Food Chem 1998; 46: 1055-58.
21. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248-54.
22. Beauchamp C, Fridovich I. Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Anal Biochem 1971; 44: 276‑87.
23. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 1976; 71: 952-58.
24. Luck H. Catalase. In: Methods of Enzymatic Analysis, Bergmeyer HU (ed). Academic Press/Verlag Chemie, New York; 1963: 885-94.
25. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86: 271-8.
26. Girolamia F. Time-dependent acetylsalicylic acid effects on liver CYP1A and antioxidant enzymes in a rat model of 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinogenesis. Toxicol Lett 2008; 181: 87-92.
27. Azarmehr N, Afshar P, Moradi M, et al. Hepatoprotective and antioxidant activity of watercress extract on acetaminophen-induced hepatotoxicity in rats. Heliyon 2019; 5: e02072.
28. Doustimotlagh AH, Kokhdan EP, Vakilpour H, et al. Protective effect of Nasturtium officinale R. Br and quercetin against cyclophosphamide-induced hepatotoxicity in rats. Mol Biol Rep 2020; 47: 5001-12.
29. Gulbahce-Mutlu E, Baltaci SB, Menevse E, Mogulkoc R, Baltaci AK. The Effect of zinc and melatonin administration on lipid peroxidation, IL-6 levels, and element metabolism in DMBA-induced breast cancer in rats. Biol Trace Elem Res 2021; 199: 1044-51.
30. Saha SK, Lee SB, Won J, et al. Correlation between oxidative stress, nutrition, and cancer initiation. Int J Mol Sci 2017; 18: E1544.
31. Zeweil MM, Sadek KM, Taha NM, El-Sayed Y, Menshawy S. Graviola attenuates DMBA-induced breast cancer possibly through augmenting apoptosis and antioxidant pathway and downregulating estrogen receptors. Environ Sci Pollut Res Int 2019; 26: 15209–17.
32. Sadeghi H, Azarmehr N, Razmkhah F, et al. The hydroalcoholic extract of watercress attenuates protein oxidation, oxidative stress, and liver damage after bile duct ligation in rats. J Cell Biochem 2019; 120: 14875-84.
33. Sun T, Gao J, Han D, Shi H, Liu X. Fabrication and characterization of solid lipid nano-formulation of astraxanthin against DMBA-induced breast cancer via Nrf-2-Keap1 and NF-kB and mTOR/Maf-1/PTEN pathway. Drug Deliv 2019; 26: 975-88.
34. Flocryk U, Lobodam A, Stachurska A, Jozkowicz A, Dulak J. Role of Nrf2 transcription factor in the cellular response to oxidative stress. Postepy Biochem 2010; 56: 147-55.
35. Kavitha K, Thiyagarajan P, Nandhini JR, Mishra R, Nagini S. Chemopreventive effects of diverse dietary phytochemicals against DMBA-induced hamster buccal pouch carcinogenesis via the induction of Nrf2-mediated cytoprotective antioxidant, detoxification, and DNA repair enzymes. Biochimie 2013; 95: 1629-39.
36. Yamamoto M, Kensler TW, Motohashi H. The Keap1-Nrf2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol Rev 2018; 98: 1169-203.
37. Konsue N, Ioannides C. Tissue differences in the modulation of rat cytochromes P450 and phase II conjugation systems by dietary doses of phenethyl isothiocyanate. Food Chem Toxicol 2008; 46: 3677-83.
38. Saravanan D, Baskaran K, Sakthisekaran D. Protective effect of thymoquinone on the liver tissues of 7, 12-dimethylbenz(a) anthracene induced experimental breast cancer rats. Asian J Pharm Clin Res 2016; 9: 197–201.
39. Ezzat SM, El-Halawany AM, Hamed AR, Abdel-Sattar E. Chapter 9-Role phytochemicals play in the activation of antioxidant response elements (AREs) and phase II enzymes and their relation to cancer progression and prevention. In: Studies in Natural Products Chemistry, Atta-ur-Rahman (ed). Elsevier, Volume 60; 2019: 345-69.