Toxicological Research

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

DOI QR Code

Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection

  • Gum, Sang Il (Department of Pharmacology, College of Oriental Medicine, Dongguk University) ;
  • Cho, Min Kyung (Department of Pharmacology, College of Oriental Medicine, Dongguk University)
  • Received : 2013.09.01
  • Accepted : 2013.09.26
  • Published : 2013.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection.

Keywords

References

  1. Watson, W.A., Litovitz, T.L., Klein-Schwartz, W., Rodgers, G.C. Jr., Youniss, J., Reid, N., Rouse, W.G., Rembert, R.S. and Borys, D. (2004) 2003 Annual report of the american association of poison control centers toxic exposure surveillance system. Am. J. Emerg. Med., 22, 335-404. https://doi.org/10.1016/j.ajem.2004.06.001
  2. Wallace, C.I., Dargan, P.I. and Jones, A.L. (2002) Paracetamol overdose: an evidence based flowchart to guide management. Emerg. Med. J., 19, 202-205. https://doi.org/10.1136/emj.19.3.202
  3. Corcoran, G.B., Racz, W.J., Smith, C.V. and Mitchell, J.R. (1985) Effects of N-acetylcysteine on acetaminophen covalent binding and hepatic necrosis in mice. J. Pharmacol. Exp. Ther., 232, 864-872.
  4. Kanter, M.Z. (2006) Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning. Am. J. Health Syst. Pharm., 63, 1821-1827. https://doi.org/10.2146/ajhp060050
  5. Dawson, A.H., Henry, D.A. and McEwen, J. (1989) Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med. J. Aust., 150, 329-331.
  6. Delanty, N. and Fitzgerald, D.J. (1996) Paracetamol poisoning: the action line and the timing of acetylcysteine therapy. Ir. Med. J., 89, 156.
  7. Goldring, C.E., Kitteringham, N.R., Elsby, R., Randle, L.E., Clement, Y.N., Williams, D.P., McMahon, M., Hayes, J.D., Itoh, K., Yamamoto, M. and Park, B.K. (2004) Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice. Hepatology, 39, 1267-1276. https://doi.org/10.1002/hep.20183
  8. Larson, A.M. (2007) Acetaminophen hepatotoxicity. Clin. Liver Dis., 11, 525-548. https://doi.org/10.1016/j.cld.2007.06.006
  9. Reid, A.B., Kurten, R.C., McCullough, S.S., Brock, R.W. and Hinson, J.A. (2005) Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J. Pharmacol. Exp. Ther., 312, 509-516.
  10. Harrill, A.H., Watkins, P.B., Su, S., Ross, P.K., Harbourt, D.E., Stylianou, I.M., Boorman, G.A., Russo, M.W., Sackler, R.S., Harris, S.C., Smith, P.C., Tennant, R., Bogue, M., Paigen, K., Harris, C., Contractor, T., Wiltshire, T., Rusyn, I. and Threadgill, D.W. (2009) Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res., 19, 1507-1515. https://doi.org/10.1101/gr.090241.108
  11. McGill, M.R., Yan, H.M., Ramachandran, A., Murray, G.J., Rollins, D.E. and Jaeschke, H. (2011) HepaRG cells: a human model to study mechanisms of acetaminophen hepatotoxicity. Hepatology, 53, 974-982. https://doi.org/10.1002/hep.24132
  12. Hinchman, C.A. and Ballatori, N. (1990) Glutathione-degrading capacities of liver and kidney in different species. Biochem. Pharmacol., 40, 1131-1135. https://doi.org/10.1016/0006-2952(90)90503-D
  13. Ghanem, C.I., Ruiz, M.L., Villanueva, S.S., Luquita, M., Llesuy, S., Catania, V.A., Bengochea, L.A. and Mottino, A.D. (2009) Effect of repeated administration with subtoxic doses of acetaminophen to rats on enterohepatic recirculation of a subsequent toxic dose. Biochem. Pharmacol., 77, 1621-1628. https://doi.org/10.1016/j.bcp.2009.02.006
  14. Villanueva, S.S., Ruiz, M.L., Ghanem, C.I., Luquita, M.G., Catania, V.A. and Mottino, A.D. (2008) Hepatic synthesis and urinary elimination of acetaminophen glucuronide are exacerbated in bile duct-ligated rats. Drug Metab. Dispos., 36, 475-480.
  15. Williams, C.D., Bajt, M.L., Farhood, A. and Jaeschke, H. (2010) Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice. Liver Int., 30, 1280-1292. https://doi.org/10.1111/j.1478-3231.2010.02284.x
  16. Gujral, J.S., Knight, T.R., Farhood, A., Bajt, M.L. and Jaeschke, H. (2002) Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol. Sci., 67, 322-328. https://doi.org/10.1093/toxsci/67.2.322
  17. McGill, M.R., Williams, C.D., Xie, Y., Ramachandran, A. and Jaeschke, H. (2012) Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol. Appl. Pharmacol., 264, 387-394. https://doi.org/10.1016/j.taap.2012.08.015
  18. Okawa, H., Motohashi, H., Kobayashi, A., Aburatani, H., Kensler, T.W. and Yamamoto, M. (2006) Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun., 339, 79-88. https://doi.org/10.1016/j.bbrc.2005.10.185
  19. Klaassen, C.D. and Reisman, S.A. (2010) Nrf2 the rescue: effects of the antioxidative/electrophilic response on the liver. Toxicol. Appl. Pharmacol., 244, 57-65. https://doi.org/10.1016/j.taap.2010.01.013
  20. Reisman, S.A., Csanaky, I.L., Aleksunes, L.M. and Klaassen, C.D. (2009) Altered disposition of acetaminophen in Nrf2-null and Keap1-knockdown mice. Toxicol. Sci., 109, 31-40. https://doi.org/10.1093/toxsci/kfp047
  21. Gum, S.I. and Cho, M.K. (2013) The amelioration of Nacetyl-p-benzoquinone imine toxicity by ginsenoside Rg3: the role of Nrf2-mediated detoxification and Mrp1/Mrp3 transports. Oxid. Med. Cell. Longevity, 2013, 957947.
  22. Aleksunes, L.M., Slitt, A.L., Maher, J.M., Augustine, L.M., Goedken, M.J., Chan, J.Y., Cherrington, N.J., Klaassen, C.D. and Manautou, J.E. (2008) Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2. Toxicol. Appl. Pharmacol., 226, 74-83. https://doi.org/10.1016/j.taap.2007.08.022
  23. Maher, J.M., Dieter, M.Z., Aleksunes, L.M., Slitt, A.L., Guo, G., Tanaka, Y., Scheffer, G.L., Chan, J.Y., Manautou, J.E., Chen, Y., Dalton, T.P., Yamamoto, M. and Klaassen, C.D. (2007) Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology, 46, 1597-1610. https://doi.org/10.1002/hep.21831
  24. Zamek-Gliszczynski, M.J., Nezasa, K., Tian, X., Kalvass, J.C., Patel, N.J., Raub, T.J. and Brouwer, K.L. (2006) The important role of Bcrp (Abcg2) in the biliary excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in mice. Mol. Pharmacol., 70, 2127-2133. https://doi.org/10.1124/mol.106.026955
  25. Enomoto, A., Itoh, K., Nagayoshi, E., Haruta, J., Kimura, T., O'Connor, T., Harada, T. and Yamamoto, M. (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci., 59, 169-177. https://doi.org/10.1093/toxsci/59.1.169
  26. Ni, H.M., Boggess, N., McGill, M.R., Lebofsky, M., Borude, P., Apte, U., Jaeschke, H. and Ding, W.X. (2012) Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. Toxicol. Sci., 127, 438-450. https://doi.org/10.1093/toxsci/kfs133
  27. Patterson, A.D., Carlson, B.A., Li, F., Bonzo, J.A., Yoo, M.H., Krausz, K.W., Conrad, M., Chen, C., Gonzalez, F.J. and Hatfield, D.L. (2013) Disruption of thioredoxin reductase 1 protects mice from acute acetaminophen-induced hepatotoxicity through enhanced Nrf2 activity. Chem. Res. Toxicol., 26, 1088-1096. https://doi.org/10.1021/tx4001013
  28. Mobasher, M.A., Gonzalez-Rodriguez, A., Santamaria, B., Ramos, S., Martin, M.A., Goya, L., Rada, P., Letzig, L., James, L.P., Cuadrado, A., Martin-Perez, J., Simpson, K.J., Muntane, J. and Valverde, A.M. (2013) Protein tyrosine phosphatase 1B modulates GSK3beta/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity. Cell Death Dis., 4, e626. https://doi.org/10.1038/cddis.2013.150
  29. Prescott, L.F., Illingworth, R.N., Critchley, J.A., Stewart, M.J., Adam, R.D. and Proudfoot, A.T. (1979) Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br. Med. J., 2, 1097-1100. https://doi.org/10.1136/bmj.2.6198.1097
  30. Parcell, S. (2002) Sulfur in human nutrition and applications in medicine. Altern. Med. Rev., 7, 22-44.
  31. Schiodt, F.V., Lee, W.M., Bondesen, S., Ott, P. and Christensen, E. (2002) Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose. Aliment. Pharmacol. Ther., 16, 707-715. https://doi.org/10.1046/j.1365-2036.2002.01224.x
  32. Al-Mustafa, Z.H., Al-Ali, A.K., Qaw, F.S. and Abdul-Cader, Z. (1997) Cimetidine enhances the hepatoprotective action of N-acetylcysteine in mice treated with toxic doses of paracetamol. Toxicology, 121, 223-228. https://doi.org/10.1016/S0300-483X(97)00069-3
  33. Gum, S.I. and Cho, M.K. (2013) Korean red ginseng extract prevents APAP-induced hepatotoxicity through metabolic enzyme regulation: The role of ginsenoside Rg3, a protopanaxadiol. Liver Int., 33, 1071-1084. https://doi.org/10.1111/liv.12046
  34. Xie, Y., Williams, C.D., McGill, M.R., Lebofsky, M., Ramachandran, A. and Jaeschke, H. (2013) Purinergic receptor antagonist A438079 protects against acetaminophen-induced liver injury by inhibiting p450 isoenzymes, not by inflammasome activation. Toxicol. Sci., 131, 325-335. https://doi.org/10.1093/toxsci/kfs283
  35. Manautou, J.E., Tveit, A., Hoivik, D.J., Khairallah, E.A. and Cohen, S.D. (1996) Protection by clofibrate against acetaminophen hepatotoxicity in male CD-1 mice is associated with an early increase in biliary concentration of acetaminophenglutathione adducts. Toxicol. Appl. Pharmacol., 140, 30-38. https://doi.org/10.1006/taap.1996.0194
  36. Hazelton, G.A., Hjelle, J.J. and Klaassen, C.D. (1986) Effects of butylated hydroxyanisole on acetaminophen hepatotoxicity and glucuronidation in vivo. Toxicol. Appl. Pharmacol., 83, 474-485. https://doi.org/10.1016/0041-008X(86)90230-9
  37. Reisman, S.A., Aleksunes, L.M. and Klaassen, C.D. (2009) Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes. Biochem. Pharmacol., 77, 1273-1282. https://doi.org/10.1016/j.bcp.2008.12.028
  38. Shelton, L.M., Park, B.K. and Copple, I.M. (2013) Role of Nrf2 in protection against acute kidney injury. Kidney Int., 47, 698-706.
  39. Chattopadhyay, R.R. (2003) Possible mechanism of hepatoprotective activity of Azadirachta indica leaf extract: part II. J. Ethnopharmacol., 89, 217-219. https://doi.org/10.1016/j.jep.2003.08.006
  40. Fakurazi, S., Sharifudin, S.A. and Arulselvan, P. (2012) Moringa oleifera hydroethanolic extracts effectively alleviate acetaminophen-induced hepatotoxicity in experimental rats through their antioxidant nature. Molecules, 17, 8334-8350. https://doi.org/10.3390/molecules17078334
  41. Shon, Y.H. and Nam, K.S. (2004) Protective effect of Moutan Cortex extract on acetaminophen-induced hepatotoxicity in mice. J. Ethnopharmacol., 90, 415-419. https://doi.org/10.1016/j.jep.2003.11.004
  42. Lee, K.J., You, H.J., Park, S.J., Kim, Y.S., Chung, Y.C., Jeong, T.C. and Jeong, H.G. (2001) Hepatoprotective effects of Platycodon grandiflorum on acetaminophen-induced liver damage in mice. Cancer Lett., 174, 73-81. https://doi.org/10.1016/S0304-3835(01)00678-4
  43. Kavitha, P., Ramesh, R., Bupesh, G., Stalin, A. and Subramanian, P. (2011) Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwa ter fish (Oreochromis mossambicus). In Vitro Cell. Dev. Biol. Anim., 47, 698-706. https://doi.org/10.1007/s11626-011-9457-9
  44. Porchezhian, E. and Ansari, S.H. (2000) Effect of liquid extract from fresh Abutilon indicum leaves and Allium cepa bulbs on paracetamol and carbontetrachloride induced hepatotoxicity. Pharmazie, 55, 702-703.
  45. Gilani, A.H. and Janbaz, K.H. (1993) Protective effect of Artemisia scoparia extract against acetaminophen-induced hepatotoxicity. Gen. Pharmacol., 24, 1455-1458. https://doi.org/10.1016/0306-3623(93)90434-Y
  46. Lin, C.C., Shieh, D.E. and Yen, M.H. (1997) Hepatoprotective effect of the fractions of Ban-zhi-lian on experimental liver injuries in rats. J. Ethnopharmacol., 56, 193-200. https://doi.org/10.1016/S0378-8741(97)00026-3
  47. Yen, F.L., Wu, T.H., Lin, L.T., Cham, T.M. and Lin, C.C. (2008) Nanoparticles formulation of Cuscuta chinensis prevents acetaminophen-induced hepatotoxicity in rats. Food Chem. Toxicol., 46, 1771-1777. https://doi.org/10.1016/j.fct.2008.01.021
  48. Gilani, A.U. and Janbaz, K.H. (1995) Studies on protective effect of Cyperus scariosus extract on acetaminophen and CCl4-induced hepatotoxicity. Gen. Pharmacol., 26, 627-631. https://doi.org/10.1016/0306-3623(94)00200-7
  49. Gilani, A.H., Janbaz, K.H. and Akhtar, M.S. (1996) Selective protective effect of an extract from Fumaria parviflora on paracetamol-induced hepatotoxicity. Gen. Pharmacol, 27, 979-983. https://doi.org/10.1016/0306-3623(95)02140-X
  50. Garba, S.H., Sambo, N. and Bala, U. (2009) The effect of the aqueous extract of Kohautia grandiflora on paracetamolinduced liver damage in albino rats. Niger. J. Physiol. Sci., 24, 17-23.
  51. Bhaskar, V.H. and Balakrishnan, N. (2010) Protective effects of Pergularia daemia roots against paracetamol and carbon tetrachloride-induced hepatotoxicity in rats. Pharm. Biol., 48, 1265-1272. https://doi.org/10.3109/13880201003730667
  52. Hau, D.K., Gambari, R., Wong, R.S., Yuen, M.C., Cheng, G.Y., Tong, C.S., Zhu, G.Y., Leung, A.K., Lai, P.B., Lau, F.Y., Chan, A.K., Wong, W.Y., Kok, S.H., Cheng, C.H., Kan, C.W., Chan, A.S., Chui, C.H., Tang, J.C. and Fong, D.W. (2009) Phyllanthus urinaria extract attenuates acetaminophen induced hepatotoxicity: involvement of cytochrome P450 CYP2E1. Phytomedicine, 16, 751-760. https://doi.org/10.1016/j.phymed.2009.01.008
  53. Lin, S.C., Chung, T.C., Ueng, T.H., Lin, Y.H., Hsu, S.H., Chiang, C.L. and Lin, C.C. (2000) The hepatoprotective effects of Solanum alatum Moench. on acetaminopheninduced hepatotoxicity in mice. Am. J. Chin. Med., 28, 105-114. https://doi.org/10.1142/S0192415X00000131
  54. Hajimehdipoor, H., Sadeghi, Z., Elmi, S., Elmi, A., Ghazi-Khansari, M., Amanzadeh, Y. and Sadat-Ebrahimi, S.E. (2006) Protective effects of Swertia longifolia Boiss. and its active compound, swerchirin, on paracetamol-induced hepatotoxicity in mice. J. Pharm. Pharmacol., 58, 277-280. https://doi.org/10.1211/jpp.58.2.0017
  55. Colle, D., Arantes, L.P., Gubert, P., da Luz, S.C., Athayde, M.L., Teixeira Rocha, J.B. and Soares, F.A. (2012) Antioxidant properties of Taraxacum officinale leaf extract are involved in the protective effect against hepatoxicity induced by acetaminophen in mice. J. Med. Food, 15, 549-556. https://doi.org/10.1089/jmf.2011.0282
  56. Subramoniam, A., Evans, D.A., Rajasekharan, S. and Pushpangadan, P. (1998) Hepatoprotective activity of Trichopus zeylanicus extract against paracetamol-induced hepatic damage in rats. Indian J. Exp. Biol., 36, 385-389.
  57. Baravalia, Y. and Chanda, S. (2011) Protective effect of Woodfordia fruticosa flowers against acetaminophen-induced hepatic toxicity in rats. Pharm. Biol., 49, 826-832. https://doi.org/10.3109/13880209.2010.550057

Cited by

  1. Protection against acetaminophen-induced acute liver failure by omentum adipose tissue derived stem cells through the mediation of Nrf2 and cytochrome P450 expression vol.23, pp.1, 2016, https://doi.org/10.1186/s12929-016-0231-x
  2. Acetaminophen-induced S-nitrosylation and S-sulfenylation signalling in 3D cultured hepatocarcinoma cell spheroids vol.5, pp.3, 2016, https://doi.org/10.1039/C5TX00469A
  3. Hepatoprotective Effect of Carboxymethyl Pachyman in Fluorouracil-Treated CT26-Bearing Mice vol.22, pp.5, 2017, https://doi.org/10.3390/molecules22050756
  4. Purification, Preliminary Characterization and Hepatoprotective Effects of Polysaccharides from Dandelion Root vol.22, pp.9, 2017, https://doi.org/10.3390/molecules22091409
  5. Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice vol.60, pp.2, 2017, https://doi.org/10.3164/jcbn.16-44
  6. Induction of Mkp-1 and Nuclear Translocation of Nrf2 by Limonoids from Khaya grandifoliola C.DC Protect L-02 Hepatocytes against Acetaminophen-Induced Hepatotoxicity vol.8, pp.1663-9812, 2017, https://doi.org/10.3389/fphar.2017.00653
  7. Pharmacogenetic insights into migraine treatment in children vol.15, pp.11, 2014, https://doi.org/10.2217/pgs.14.104
  8. The Protective Effect of Grape-Seed Proanthocyanidin Extract on Oxidative Damage Induced by Zearalenone in Kunming Mice Liver vol.17, pp.6, 2016, https://doi.org/10.3390/ijms17060808
  9. Nrf2, the Master Regulator of Anti-Oxidative Responses vol.18, pp.12, 2017, https://doi.org/10.3390/ijms18122772
  10. Astragaloside IV Attenuates Acetaminophen-Induced Liver Injuries in Mice by Activating the Nrf2 Signaling Pathway vol.23, pp.8, 2018, https://doi.org/10.3390/molecules23082032
  11. 4-Hydroxyphenylacetic Acid Prevents Acute APAP-Induced Liver Injury by Increasing Phase II and Antioxidant Enzymes in Mice vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.00653
  12. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury vol.14, pp.1, 2014, https://doi.org/10.1186/1472-6882-14-494
  13. Xiaochaihutang Inhibits the Activation of Hepatic Stellate Cell Line T6 Through the Nrf2 Pathway vol.9, pp.1663-9812, 2019, https://doi.org/10.3389/fphar.2018.01516
  14. Corilagin alleviates acetaminophen-induced hepatotoxicity via enhancing the AMPK/GSK3β-Nrf2 signaling pathway vol.17, pp.1, 2019, https://doi.org/10.1186/s12964-018-0314-2
  15. Grape Seed Proanthocyanidin Extract Alleviates AflatoxinB1-Induced Immunotoxicity and Oxidative Stress via Modulation of NF-κB and Nrf2 Signaling Pathways in Broilers vol.11, pp.1, 2019, https://doi.org/10.3390/toxins11010023