Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Hepatoprotective effect of Centella asiatica 50% ethanol extract against acetaminophen-induced acute liver injury in BALB/c mice

  • Park, Dae Won (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Jeon, Hyelin (BioMedical Research Institute, Kyung Hee University) ;
  • Kwon, Jeong Eun (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Lee, Young Geun (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • So, Rina (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Choe, Tae Hwan (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University) ;
  • Jeong, Yong Joon (Genencell Co. Ltd.) ;
  • Kang, Se Chan (Department of Oriental Medicine Biotechnology, College of Life Sciences, Kyung Hee University)
  • Received : 2020.05.19
  • Accepted : 2020.08.21
  • Published : 2021.04.15
⟨ Previous Next ⟩

Abstract

N-acetyl-p-aminophenol (acetaminophen, APAP) is a well-known component of analgesic and antipyretic monotherapy products. However, exceeding the recommended dose can lead to serious injury to the liver. We conducted this study to determine the potential of Centella asiatica as a natural substance to protect against APAP-induced liver injury. When acute hepatotoxicity was induced in mice by APAP overdose, their liver weight decreased significantly (p<0.05). However, mice treated with C. asiatica 50% ethanol extract (CA-HE50, 200 mg/kg) for a week before induction of hepatotoxicity by APAP had similar liver weights to those of mice in which hepatotoxicity was not induced. In particular, levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, which are biomarkers of liver injury, were significantly increased by APAP and dose-dependently decreased by CA-HE50 (p<0.05). Glutathione and malondialdehyde, indicators of oxidative stress, were significantly changed by APAP and CA-HE50 (p<0.05). In addition, hepatic necrosis and expression of genes encoding pro-inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, and IL-4) induced by APAP were inhibited by CA-HE50, and these results were dose-dependent. Through our in vivo studies, we found that CA-HE50 can help prevent APAP-induced hepatic tissue injury in BALB/c mice. Furthermore, CA-HE50 was effective at protecting RAW 264.7 cells from lipopolysaccharide-induced cytotoxicity and inhibiting the release of nitric oxide from these cells; in particular, asiaticoside was found to be a key component of CA-HE50 responsible for these effects. Therefore, we suggest that CA-HE50 has potential applications in functional health foods and drugs.

Keywords

Acknowledgement

This work was supported by the Korean Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry (IPET) through the High Value-Added Food Technology Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) (117050-3).

References

  1. Jaeschke H, Xie Y, McGill MR (2014) APAP-induced liver injury: from animal models to humans. J Clin Transl Hepatol 2:153-161. https://doi.org/10.14218/JCTH.2014.00014
  2. Woolbright BL, Jaeschke H (2017) Role of the inflammasome in APAP-induced liver injury and acute liver failure. J Hepatol 66:836-848. https://doi.org/10.1016/j.jhep.2016.11.017
  3. Bunchorntavakul C, Reddy KR (2013) APAP-related hepatotoxicity. Clin Liver Dis 17:587-607. https://doi.org/10.1016/j.cld.2013.07.005
  4. Herndon CM, Dankenbring DM (2014) Patient perception and knowledge of APAP in a large family medicine service. J Pain Palliat Care Pharmacother 28:109-116. https://doi.org/10.3109/15360288.2014.908993
  5. Clark R, Fisher JE, Sketris IS, Johnston GM (2012) Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study. BMC Clin Pharmacol 12:11. https://doi.org/10.1186/1472-6904-12-11
  6. Lancaster EM, Hiatt JR, Zarrinpar A (2014) APAP hepatotoxicity: an updated review. Arch Toxicol 89:193-199. https://doi.org/10.1007/s00204-014-1432-2
  7. Kane AE, Mitchell SJ, Mach J (2016) APAP hepatotoxicity in mice: effect of age, frailty and exposure type. Exp Gerontol 73:95-106. https://doi.org/10.1016/j.exger.2015.11.013
  8. Murray KF, Hadzic N, Wirth S, Bassett M, Kelly D (2008) Drug-related hepatotoxicity and acute liver failure. J Pediatr Gastroenterol Nutr 47:395-405. https://doi.org/10.1097/MPG.0b013e3181709464
  9. Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from APAP hepatotoxicity. Drug Metab Rev 44:88-106. https://doi.org/10.3109/03602532.2011.602688
  10. Nourjah P, Ahmad SR, Karwoski C, Willy M (2006) Estimates of APAP (Paracetomal)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf 15:398-405. https://doi.org/10.1002/pds.1191
  11. Miller LL, Bly CG, Watson ML, Bale WF (1951) The dominant role of the liver in plasma protein synthesis, a direct study of the isolated perfused rat liver with the aid of lysine-ϵ-C14. J Exp Med 94:431-453. https://doi.org/10.1084/jem.94.5.431
  12. Shaabana HAE, El-Ghoraba AH, Shibamotob T (2012) Bioactivity of essential oils and their volatile aroma components: review. J Essent Oil Res 24:203-212. https://doi.org/10.1080/10412905.2012.659528
  13. Jamil SS, Nizami Q, Salam M (2007) Centella asiatica (Linn.) urban o' a review. Nat Pro Radiance 6:158-170. https://doi.org/10.1084/jem.94.5.431
  14. Zahara K, Bibi Y, Tabassum S (2014) Clinical and therapeutic benefits of Centella asiatica. Pure Appl Biol 3:152-159. https://doi.org/10.19045/bspab.2014.34004
  15. Fontana RJ (2008) Acute Liver Failure including Aceteaminophen overdose. Med Clin North Am 92:761-794. https://doi.org/10.1016/j.mcna.2008.03.005
  16. Roberts DW, Bucci TJ, Benson RW, Warbritton AR, McRae TA, Pumford NR, Hinson JA (1991) Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity. Am J Pathol 138:359-371.
  17. McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H (2012) The mechanism underlying APAP-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 122:1574-1583. https://doi.org/10.1172/JCI59755
  18. Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, Forster J, Jaeschke H (2014) Mechanisms of APAP-induced cell death in primary human hepatocytes. Toxicol Appl Pharmacol 279:266-274. https://doi.org/10.1016/j.taap.2014.05.010
  19. Kato GJ, McGowan V, Machado RF, Little JA, Taylor J, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT (2006) Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 107:2279-2285. https://doi.org/10.1182/blood-2005-06-2373
  20. Tomasi TB Jr, Tisdale WA (1964) Serum gamma-globulins in acute and chronic liver diseases. Nature 201:834-835. https://doi.org/10.1038/201834a0
  21. Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16:26087-260124. https://doi.org/10.3390/ijms161125942
  22. Liu WX, Jia FL, He YY, Zhang BX (2012) Protective effects of 5-methoxypsoralen against APAP induced hepatotoxicity in mice. World J Gastroenterol 18:2197-2202. https://doi.org/10.3748/wjg.v18.i18.2197
  23. Milton PS, Muthumani M, Shagirtha K (2013) Quercetin potentially attenuates cadmium induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. Eur Rev Med Pharmacol Sci 17:582-595. https://doi.org/10.1007/s12012-013-9227-x
  24. Wan J, Gong X, Jiang R, Zhang Z, Zhang L (2013) Antipyretic and anti-inflammatory effects of asiaticoside in lipopolysaccharide-treated rat through up-regulation of heme oxygenase-1. Phytother Res 27:1136-1142. https://doi.org/10.1002/ptr.4838
  25. Shukla A, Rasik AM, Dhawan BN (1999) Asiaticoside-induced elevation of antioxidant levels in healing wounds. Phytother Res 13:50-54. https://doi.org/10.1002/(SICI)1099-1573(199902)13:1<50::AID-PTR368>3.0.CO;2-V
  26. Shao W, Cao X, Shen L, Zhang F, Yu B (2017) A convergent synthesis of the triterpene saponin asiaticoside. Asian J Org Chem 6:1270-1276. https://doi.org/10.1002/ajoc.201700153
  27. Huang YH, Zhang SH, Zhen RX, Xu XD, Zhen YS (2004) Asiaticoside inducing apoptosis of tumor cells and enhancing anti-tumor activity of vincristine. Ai Zheng 23:1599-1604.
  28. Park DW, Jeon H, So R, Kang SC (2020) Centella asiatica extract prevents visual impairment by promoting the production of rhodopsin in the retina. Nutr Res Pract 14:203-217. https://doi.org/10.4162/nrp.2020.14.3.203
  29. Nourjah P, Ahmad SR, Pharm CK, Willy M (2006) Estimates of acetaminophen (paracetomal)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf 15:398-405. https://doi.org/10.1002/pds.1191
  30. Rubin JB, Hameed B, Gottfried M, Lee WM, Sarkar M (2018) Acute liver failure study group. Acetaminophen-induced acute liver failure is more common and more severe in women. Clin Gastroenterol Hepatol 16:936-946. https://doi.org/10.1016/j.cgh.2017.11.042
  31. McNulty R, Lim JME, Chandru P, Gunja N (2018) Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose. Clin Toxicol (Phila) 56:618-621. https://doi.org/10.1080/15563650.2017.1408812
  32. Uchida NS, Silva-Filho SE, Aguiar RP, Wiirzler LAM, Cardia GFE, Cavalcante HAO, Silva-Comar FMS, Becker TCA, Silva EL, Bersani-Amado CA, Cuman RKN (2017) Protective effect of cymbopogon citratus essential oil in experimental model of acetaminophen-induced liver injury. Am J Chin Med 45:515-532. https://doi.org/10.1142/S0192415X17500318
  33. Yan M, Huo Y, Yin S, Hu H (2018) Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol 17:274-283. https://doi.org/10.1016/j.redox.2018.04.019
  34. Du K, Ramachandran A, Jaeschke H (2016) Oxidative stress during acetaminophen hepatotoxicity: sources, pathophysiological role and therapeutic potential. Redox Biol 10:148-156. https://doi.org/10.1016/j.redox.2016.10.001
  35. Liang H, Feng Y, Cui R, Qiu M, Zhang J, Liu C (2018) Simvastatin protects against acetaminophen-induced liver injury in mice. Biomed Pharmacother 98:916-924. https://doi.org/10.1016/j.biopha.2017.12.076
  36. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313-326. https://doi.org/10.1089/jir.2008.0027
  37. Wang L, Li X, Chen C (2018) Inhibition of acetaminophen-induced hepatotoxicity in mice by exogenous thymosinβ4 treatment. Int Immunopharmacol 61:20-28. https://doi.org/10.1016/j.intimp.2018.05.011

Cited by

  1. A Comparative Study of the Hepatoprotective Effect of Centella asiatica Extract (CA-HE50) on Lipopolysaccharide/d-galactosamine-Induced Acute Liver Injury in C57BL/6 Mice vol.13, pp.11, 2021, https://doi.org/10.3390/nu13114090
  2. A Randomized, Double-Blind, Placebo-Controlled Parallel Study on the Efficacy and Safety of Centella asiatica L. Extract for Reducing Alanine Transaminase (ALT) Level in Subjects with Elevated ALT vol.11, pp.23, 2021, https://doi.org/10.3390/app112311498