[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.5487/TR.2013.29.3.165

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)

Publication Information

Toxicological Research / v.29, no.3, 2013 , pp. 165-172 More about this Journal

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

Acetaminophen; Hepatotoxicity; Nrf2; Natural product;

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Times Cited By KSCI : 1 (Citation Analysis)

Reference
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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. DOI ScienceOn
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. DOI
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. DOI ScienceOn
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. DOI ScienceOn
8	Larson, A.M. (2007) Acetaminophen hepatotoxicity. Clin. Liver Dis., 11, 525-548. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
12	Hinchman, C.A. and Ballatori, N. (1990) Glutathione-degrading capacities of liver and kidney in different species. Biochem. Pharmacol., 40, 1131-1135. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
26	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. DOI
27	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. DOI ScienceOn
28	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. DOI ScienceOn
29	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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
34	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. DOI ScienceOn
35	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. DOI
36	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. DOI ScienceOn
37	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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
42	Gilani, A.H. and Janbaz, K.H. (1993) Protective effect of Artemisia scoparia extract against acetaminophen-induced hepatotoxicity. Gen. Pharmacol., 24, 1455-1458. DOI ScienceOn
43	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. DOI ScienceOn
44	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. DOI ScienceOn
45	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.
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn
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	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. DOI ScienceOn
52	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. DOI ScienceOn
53	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. DOI ScienceOn
54	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. DOI ScienceOn
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. DOI ScienceOn
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. DOI ScienceOn

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