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Antioxidative and Protective Actions of Apigenin in a Paracetamol-Induced Hepatotoxicity Rat Model

  • Aleksandar Rašković
  • Slobodan Gigov
  • Ivan Čapo
  • Milica Paut Kusturica
  • Boris Milijašević
  • Sunčica Kojić-Damjanov
  • Nikola Martić
Original Research Article

Abstract

Background and Objectives

Apigenin is known to have various pharmacological properties without causing significant toxicity; however, hepatoprotective effect of apigenin is not often reported. The aim of our study was to investigate if the alterations in lipid peroxidation and antioxidant status are in favor to prove the efficacy of apigenin against paracetamol-induced hepatotoxicity.

Methods

The effect of apigenin on paracetamol-induced hepatotoxicity in rats was examined by determining biochemical parameters, histological assessment and oxidative status in liver homogenates.

Results

The treatment of animals with both apigenin and paracetamol attenuates the parameters of hepatotoxicity, especially for ALT and ALP activity which was significantly lower compared to groups of animals treated with saline and paracetamol. Hepatotoxicity induced by toxic dose of paracetamol was revealed also by notable histopathological alterations, which were not observed in the group treated with paracetamol together with apigenin. Apigenin also prevented paracetamol-induced increase in malondialdehyde (MDA) level. The activities of both CAT (catalase) and GR (glutathione reductase) enzymes after the toxic dose of paracetamol were significantly increased in the liver homogenates, compared to control group. Apigenin reversed these parameters near to values of control group.

Conclusions

The result of our study indicates that apigenin inhibits the level of lipid peroxidation and significantly increases the enzyme antioxidant defense mechanisms in paracetamol-induced hepatotoxicity in rats.

Keywords

Paracetamol Glutathione Reductase Apigenin Liver Homogenate Toxic Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Conflict of interest

Author Aleksandar Rašković, Author Slobodan Gigov, Author Ivan Čapo, Author Milica Paut Kusturica, Author Boris Milijašević, Author Sunčica Kojić-Damjanov, and Author Nikola Martić declare that they have no conflict of interest.

Funding

This work was supported by Provincial Secretariat for Higher Education and Scientific Research (Project No. 142-451-3680/2016-03) and by the Ministry of Science and Technological Development, Republic of Serbia (Project No. 41012).

Ethical Approval

Animal care and all experimental procedures were performed in agreement with the UK Animals Act 1986 and associated guidelines, the EEC Directive of 1986 (86/609/EEC). This study was approved by the Ethical Committee of the University of Novi Sad (Approval No. 01-160/9).

References

  1. 1.
    Bhakuni GS, Bedi O, Bariwal J, Deshmukh R, Kumar P. Animal models of hepatotoxicity. Inflamm Res. 2016;65:13–24.CrossRefPubMedGoogle Scholar
  2. 2.
    Gu X, Manautou JE. Molecular mechanisms underlying chemical liver injury. Expert Rev Mol Med. 2012;14:e4. doi: 10.1017/S1462399411002110.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Corsini A, Bortolini M. Drug-induced liver injury: the role of drug metabolism and transport. J Clin Pharmacol. 2013;53:463–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Madrigal-Santillán E, Madrigal-Bujaidar E, Álvarez-González I, Sumaya-Martínez MT, Gutiérrez-Salinas J, Bautista M, Morales-González Á, García-Luna y González-Rubio M, Aguilar-Faisal JL, Morales-González JA. Review of natural products with hepatoprotective effects. World J Gastroenterol. 2014;20:14787–804.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rašković A, Milanović I, Pavlović N, Ćebović T, Vukmirović S, Mikov M. Antioxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its hepatoprotective potential. BMC CAM. 2014;14:1.Google Scholar
  6. 6.
    Rašković A, Pavlović N, Kvrgić M, Sudji J, Mitić G, Čapo I, Mikov M. Effects of pharmaceutical formulations containing thyme on carbon tetrachloride-induced liver injury in rats. BMC CAM. 2015;15:1.Google Scholar
  7. 7.
    Zhang A, Sun H, Wang X. Recent advances in natural products from plants for treatment of liver diseases. Eur J Med Chem. 2013;63:570–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J. 2013. doi: 10.1155/2013/162750.Google Scholar
  9. 9.
    Lefort ÉC, Blay J. Apigenin and its impact on gastrointestinal cancers. Mol Nutr Food Res. 2013;57(1):126–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Shukla S, Gupta S. Apigenin: a promising molecule for cancer prevention. Pharm Res. 2010;27:962–78.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yang J, Wang XY, Xue J, Gu ZL, Xie ML. Protective effect of apigenin om mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity. Food Funct. 2013;4:939–43.CrossRefPubMedGoogle Scholar
  12. 12.
    Tsaroucha AK, Tsiaousidou A, Ouyounidis N, Tsalkidou E, Lambropoulou M, Giakoustidis D, et al. Intraperitoneal administration od apigenin in liver ischemia/reperfusion injury protective effects. Saudi J Gastroenterol. 2016;22(6):415–22.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol. 1978;52:302–10.CrossRefPubMedGoogle Scholar
  14. 14.
    Beers RF, Sizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem. 1952;195:133–40.PubMedGoogle Scholar
  15. 15.
    Beutler E. Red cell metabolism: a manual of biochemical methods. New York: Grune & Stratton Inc; 1984.Google Scholar
  16. 16.
    Goldberg D, Spooner R. Glutathione reductase. Methods Enzym Anal. 1983;3:258–65.Google Scholar
  17. 17.
    Ajiboye T. Standardized extract of Vitex doniana Sweet stalls protein oxidation, lipid peroxidation and DNA fragmention in acetaminophen-induced hepatotoxicity. J Ethnopharmacol. 2015;164:273–82.CrossRefPubMedGoogle Scholar
  18. 18.
    Pápay ZE, Antal I. Study on the antioxidant activity during the formulation of biological active ingredient. ESJ. 2014;3:252–7.Google Scholar
  19. 19.
    Pandit A, Sachdeva T, Bafna P. Drug-induced hepatotoxicity: a review. J Appl Pharm Sci. 2012;2:233–43.Google Scholar
  20. 20.
    Kleinman J, Breitenfield R, Roth D. Acute renal failure associated with acetaminophen ingestion: report of a case and review of the literature. Clin Nephrol. 1980;14:201–5.PubMedGoogle Scholar
  21. 21.
    Nelson SD, Bruschi SA. Mechanisms of acetaminophen-induced liver disease. In: Kaplowitz N, De Leve LD, editors. Drug-induced liver disease. New York: Marcel Dekker; 2002. p. 287–325.Google Scholar
  22. 22.
    Ilavenil S, Al-Dhabi NA, Srigopalram S, Ock Kim Y, Agastian P, Baru R, Choi KC, Valan Arasu M. Acetaminophen induced hepatotoxicity in wistar rats—a proteomic approach. Molecules. 2016;21:161.CrossRefPubMedGoogle Scholar
  23. 23.
    Ali F, Naz F, Jyoti S, Siddique YH. Protective effect of apigenin against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in albino rats. Mutat Res, Genet Toxicol Environ Mutagen. 2014;767:13–20.CrossRefGoogle Scholar
  24. 24.
    Ahlenstiel T, Burkhardt G, Köhler H, Kuhlmann MK. Bioflavonoids attenuate renal proximal tubular cell injury during cold preservation in Euro-Collins and University of Wisconsin solutions. Kidney Int. 2003;63:554–63.CrossRefPubMedGoogle Scholar
  25. 25.
    Chakravarthi S, Haleagrahara N, Wen CF, Lee N, Thani P. C-myc regulation and apoptosis in assessing the beneficial effect of apigenin in cyclosporine induced nephrotoxicity. Res J Pharmacol. 2010;4:15–20.CrossRefGoogle Scholar
  26. 26.
    Chakravarthi S, Chiang LL, Nagaraja HS. Histopathological study and immunohistochemical expression of TGF-β in the role of 4′,5′,7′ trihydroxyflavone in acute renal failure. J Clin Exp Pathol. 2012;2:5.Google Scholar
  27. 27.
    Esterbauer H, Schaur R Jr, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1990;11:81–128.CrossRefGoogle Scholar
  28. 28.
    Singh JPV, Selvendiran K, Banu SM, Padmavathi R, Sakthisekaran D. Protective role of Apigenin on the status of lipid peroxidation and antioxidant defense against hepatocarcinogenesis in Wistar albino rats. Phytomedicine. 2004;11:309–14.CrossRefPubMedGoogle Scholar
  29. 29.
    Mora A, Paya M, Rios J, Alcaraz M. Structure-activity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation. Biochem Pharmacol. 1990;40:793–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Cholbi M, Paya M, Alcaraz M. Inhibitory effects of phenolic compounds on CCl4-induced microsomal lipid peroxidation. Experientia. 1991;47:195–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Seifried HE, Anderson DE, Fisher EI, Milner JA. A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem. 2007;18:567–79.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhu R, Wang Y, Zhang L, Guo Q. Oxidative stress and liver disease. Hepatol Res. 2012;42:741–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Halliwell B, Gutteridge J. Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J. 1984;219:1.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Aleksandar Rašković
    • 1
  • Slobodan Gigov
    • 1
  • Ivan Čapo
    • 1
  • Milica Paut Kusturica
    • 1
  • Boris Milijašević
    • 1
  • Sunčica Kojić-Damjanov
    • 1
  • Nikola Martić
    • 1
  1. 1.Faculty of MedicineNovi SadSerbia

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