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Submitted
January 29, 2021
Accepted
December 31, 2021
Published
December 31, 2021
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Abstract

Acetaminophen is widely used as a fever and pain reliever drug. However, acetaminophen intoxication was common and responsible for thousands of acetaminophen-induced liver injury (AILI) cases worldwide. It was understood that glutathione (GSH) depletion causes a deposit of acetaminophen metabolites which are toxic to liver cells. N-acetylcysteine (NAC), used as acetaminophen intoxication therapy, has been reported to cause side effects such as nausea, vomiting, and anaphylactic reaction. This narrative review aimed to discuss other potential candidates in AILI management. The biomolecular approach was used to investigate onion skin in-depth and holistic discussion. According to the results, onion peel extract is rich in flavonoids (quercetin and kaempferol) and potentially be a candidate in the management of AILI through proposed mechanisms such as restoration of reduced glutathione (GSH), inhibition of cytochrome P450 (CYP) enzymes, upregulation of uridine 5'-diphospho-glucuronosyltransferase (UGT) enzyme, and inhibition of TLR4 activity. 

Keywords

Red onion skin Acetaminophen-induced Liver Injury (AILI) Glutathione (GSH) Hepatoprotector Quercetin Kaempferol

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How to Cite
Ardianto, R. K., Abimanyu, L. D., Waliyuddin, A. W., Noerwahjono, A., Lestari, D. Y., & Safithri, F. (2021). The potency of red onion skin flavonoids in acetaminophen-induced liver injury management: A biomolecular review. JKKI : Jurnal Kedokteran Dan Kesehatan Indonesia, 12(3), 285–293. https://doi.org/10.20885/JKKI.Vol12.Iss3.art12
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References

  1. Ghanem CI, Maria J., Manautou J., Mottino A. ACETAMINOPHEN; FROM LIVER TO BRAIN: NEW INSIGHTS INTO DRUG PHARMACOLOGICAL ACTION AND TOXICITY. Pharmacol Res. 2017;109(July):119–31.
  2. Shiffman S, Battista DR, Kelly JP, Malone MK, Weinstein RB, Kaufman DW. Prevalence of exceeding maximum daily dose of paracetamol, and seasonal variations in cold-flu season. Br J Clin Pharmacol. 2018;84(6):1250–7.
  3. Ishitsuka Y, Kondo Y, Kadowaki D. Toxicological Property of Acetaminophen?: The Dark Side of a Safe Antipyretic / Analgesic Drug?? Biol Pharm Bull. 2020;43(2):195–206.
  4. Tittarelli R, Pellegrini M, Scarpellini MG, Marinelli E, Bruti V, Di Luca NM, et al. Hepatotoxicity of paracetamol and related fatalities. Eur Rev Med Pharmacol Sci. 2017;21(1):95–101.
  5. Pholmoo N, Bunchorntavakul C. Characteristics and Outcomes of Acetaminophen Overdose and Hepatotoxicity in Thailand. J Clin Transl Hepatol. 2019;7:132–9.
  6. Piotrowska N, Klukowska-r J, Lehmann B, Krummrey G, Haschke M, Exadaktylos AK, et al. Presentations Related to Acute Paracetamol Intoxication in an Urban Emergency Department in Switzerland. Emerg Med Int. 2019;2019.
  7. Altyar A, Kordi L, Skrepnek G. Clinical and economic characteristics of emergency department visits due to acetaminophen toxicity in the USA. BMJ Open. 2015;5.
  8. Rubin JB, Hameed B, Gottfried M, Lee WM, Sarkar M, Francisco S, et al. Acetaminophen-induced Acute Liver Failure is More Common and More Severe in Women. Clin Gastroenterol Hepatol. 2018;16(6):936–46.
  9. Ramachandran A, Jaeschke H. Acetaminophen Hepatotoxicity. Semin Liver Dis. 2019;39(2):221–34.
  10. Hey P, Hanrahan TP, Sinclair M, Testro AG, Angus PW, Peterson A, et al. Epidemiology and outcomes of acute liver failure in Australia. World J Hepatol. 2019;11(7):586–95.
  11. Mazaleuskaya LL, Sangkuhl K, Thorn CF, Fitzgerald GA, Altman RB, Klein TE. PharmGKB summary?: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015;25:416–26.
  12. Yan M, Huo Y, Yin S, Hu H. Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions. Redox Biol [Internet]. 2018;17(April):274–83. Available from: https://doi.org/10.1016/j.redox.2018.04.019
  13. Al C, Gluud C, Brok J, Na B, Al C, Gluud C, et al. Interventions for paracetamol ( acetaminophen ) overdose ( Review ). Cochrane Database Syst Rev. 2018;(2).
  14. Bijak M. Silybin, a Major Bioactive Component of Milk Thistle ( Silybum marianum L. Gaernt.)—Chemistry, Bioavailability, and Metabolism. Molecules. 2017;22:1–11.
  15. Freitag AF, Fernando G, Cardia E, Ambrósio B, Aguiar RP, Silva-comar FMDS, et al. Hepatoprotective Effect of Silymarin ( Silybum marianum ) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats. Evidence-Based Complement Altern Med. 2015;2015.
  16. Boadi WY, Amartey PK, Lo A, Boadi WY, Amartey PK, Lo A, et al. Effect of quercetin , genistein and kaempferol on glutathione and glutathione-redox cycle enzymes in 3T3-L1 preadipocytes glutathione-redox cycle enzymes in 3T3-L1 preadipocytes. Drug Chem Toxicol. 2015;0545(September).
  17. Dong L, Yin L, Quan H, Chu Y, Lu J. Hepatoprotective Effects of Kaempferol-3-O-a-L- Arabinopyranosyl-7-O-a-L-Rhamnopyranoside on D-Galactosamine and Lipopolysaccharide Caused Hepatic Failure in Mice. Molecules. 2017;22.
  18. Faras AA El, Elsawaf AL. Hepatoprotective activity of quercetin against paracetamol- induced liver toxicity in rats. Tanta Med J. 2017;45:92–8.
  19. Zang Y, Zhang D, Yu C, Jin C, Igarashi K. Antioxidant and hepatoprotective activity of kaempferol 3-O-ß-d- (2,6-di-O-a-l-rhamnopyranosyl)galactopyronoside against carbon tetrachloride-induced liver injury in mice. Food Sci Biotechnol. 2017;26(4):1071–6.
  20. Shi GQ, Yang J, Liu J, Liu SN, Song HX, Zhao WE, et al. Isolation of flavonoids from onion skin and their effects on K562 cell viability. Bangladesh J Pharmacol. 2016;11:18–25.
  21. Shi-lin Z, Peng D, Yu-chao XU, Jian-jun W. Quantification and analysis of anthocyanin and flavonoids compositions , and antioxidant activities in onions with three different colors. 2016;15(9):2175–81.
  22. Kwak JH, Seo JM, Kim NH, Arasu MV, Kim S, Yoon MK, et al. Variation of quercetin glycoside derivatives in three onion (Allium cepa L.) varieties. Saudi J Biol Sci. 2017;24(6):1387–91.
  23. Ivan IMS, Vesna MS. Modelling and optimization of quercetin extraction and biological activity of quercetin-rich red onion skin extract from Southeastern Serbia. J Food Nutr Res. 2018;57(1):15–26.
  24. Pareek S, Sagar NA, Sharma S, Kumar V. Onion ( Allium cepa L .). Fruit Veg Phytochem Chem Hum Heal. 2017;II(May).
  25. Subramanya SB, Venkataraman B, Fizur M, Meeran N. Therapeutic Potential of Plants and Plant Derived Phytochemicals against Acetaminophen-Induced Liver Injury. Int J Mol Sci. 2018;1–43.
  26. El-Saber Batiha G, Beshbishy AM, Ikram M, Mulla ZS, Abd El-Hack ME, Taha AE, et al. The pharmacological activity, biochemical properties, and pharmacokinetics of the major natural polyphenolic flavonoid: Quercetin. Foods. 2020;9(3).
  27. Salehi B, Machin L, Monzote L, Shari J, Ezzat SM, Salem MA, et al. Therapeutic Potential of Quercetin?: New Insights and Perspectives for Human Health. ACS Omega. 2020;5:11849–72.
  28. Wang Y, Tang C, Zhang H. Hepatoprotective effects of kaempferol 3- O -rutinoside and kaempferol 3- O -glucoside from Carthamus tinctorius L . on CCl 4 -induced oxidative liver injury in mice. J Food Drug Anal [Internet]. 2015;23(2):310–7. Available from: http://dx.doi.org/10.1016/j.jfda.2014.10.002
  29. Dabeek WM, Marra MV. Dietary quercetin and kaempferol: Bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients. 2019;11(10).
  30. Ren JIE, Lu Y, Qian Y, Chen B, Wu TAO, Ji G. Recent progress regarding kaempferol for the treatment of various diseases ( Review ). Exp Ther Med. 2019;18:2759–76.
  31. Cao L, Kwara A, Greenblatt DJ. Metabolic interactions between acetaminophen ( paracetamol ) and two flavonoids , luteolin and quercetin , through in-vitro inhibition studies. J Pharm Pharmacol. 2017;1–11.
  32. Pingili R, Challa SR, Pawar AK. Quercetin reduced the formation of N - acetyl - p - benzoquinoneimine , a toxic metabolite of paracetamol in rats and isolated rat hepatocytes. Phyther Res. 2019;33(March):1770–83.
  33. Tsai M, Hong WS, Wang Y, Lai Y, Tsou H, Liou G. Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation , UGT1A1 activation , and attenuation of oxidative stress , inflammation and apoptosis ... Kaempferol protects against propacetamol-induced acute liver injury. Toxicol Lett [Internet]. 2018;290(March 2018):97–109. Available from: https://doi.org/10.1016/j.toxlet.2018.03.024
  34. Bian Y, Liu P, Zhong JIA, Hu Y, Fan Y. Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS - induced rat intestinal microvascular endothelial cells. Mol Med Rep. 2019;19:1958–64.
  35. Li W, Yang G, Zhu Q, Zhong X, Nie Y, Li X, et al. TLR4 promotes liver inflammation by activating the JNK pathway. Eur Rev Med Pharmacol Sci. 2019;23:7655–62.
  36. El-shafey MM, Abd-allah GM, Mohamadin AM, Harisa GI, Mariee AD. Quercetin protects against acetaminophen-induced hepatorenal toxicity by reducing reactive oxygen and nitrogen species. Pathophysiology [Internet]. 2015;22(1):49–55. Available from: http://dx.doi.org/10.1016/j.pathophys.2014.12.002
  37. Li C, Zhang W, Choi J, Frei B. Quercetin affects glutathione levels and redox ratio in human aortic endothelial cells not through oxidation but formation and cellular export of quercetin-glutathione conjugates and upregulation of glutamate-cysteine ligase. Redox Biol [Internet]. 2016;9:220–8. Available from:http://dx.doi.org/10.1016/j.redox.2016.08.012
  38. Jin Y, Huang Z, Li L, Yang Y, Wang C, Wang Z, et al. Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2 / GCL / GSH antioxidant signaling pathway. Acta Pharmacol Sinta. 2018;40(June):75–85.
  39. Dong Y, Hou Q, Lei J, Wolf PG, Ayansola H, Zhang B. Quercetin Alleviates Intestinal Oxidative Damage Induced by H2O2 via Modulation of GSH: In Vitro Screening and In Vivo Evaluation in a Colitis Model of Mice. ACS Omega. 2020;5:8334–46.
  40. Dominko K, Ðikic D. Glutathionylation?: a regulatory role of glutathione in physiological processes. Arch Ind Hyg Toxicol. 2018;69(March):1–24.
  41. Teskey G, Abrahem R, Cao R. Glutathione as a Marker for Human Disease [Internet]. Vol. 87, Advances in Clinical Chemistry. Elsevier Ltd; 2018. 141–159 p. Available from: https://doi.org/10.1016/bs.acc.2018.07.004
  42. Gaucher C, Boudier A, Bonetti J, Clarot I, Leroy P, Parent M. Glutathione?: Antioxidant Properties Dedicated to to Nanotechnologies Nanotechnologies. Antioxidants. 2018;7(May).
  43. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity?: a Comprehensive Update. J Clin Transl Hepatol. 2016;4:131–42.
  44. Singh D, Cho WC, Upadhyay G. Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants?: An Overview. Front Physiol. 2016;6(January):1–18.
  45. Caparrotta TM, Antoine DJ, Dear JW, Antoine DJ. Are some people at increased risk of paracetamol-induced liver injury?? A critical review of the literature. Eur J Clin Pharmacol. 2018;74:147–60.