title: Comparison of the protective actions of N-acetylcysteine, hypotaurine and taurine against acetaminophen-induced hepatotoxicity in the rat.
abstract: When used in overdoses, acetaminophen (APAP) is a common cause of morbidity and mortality in humans. At present, N-acetylcysteine (NAC) is the antidote of choice for acetaminophen overdoses. Prompt administration of NAC can prevent the deleterious actions of APAP in the liver. In view of the similarities in antioxidant effects demonstrated by NAC, hypotaurine (HYTAU) and taurine (TAU) in this and other our laboratories, the present study was undertaken to compare these compounds for the ability to attenuate plasma and liver biochemical changes associated with a toxic dose of APAP. For this purpose, fasted male Sprague-Dawley rats, 225-250 g in weight, were intraperitoneally treated with APAP (800 mg/kg), NAC, HYTAU or TAU (2.4 mM/kg) followed 30 min later by APAP, or 50% PEG 400 (the vehicle for APAP). At 6 hr after APAP administration, all animals were sacrificed by decapitation and their blood and livers collected. The plasma fractions were analyzed for indices of liver damage (alanine transaminase, aspartate transaminase, lactate dehydrogenase), levels of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione, and activities of glutathione reductase (GR), glutathione S-transferase (GST) and gamma-glutamylcisteinyl synthetase (GCS). Suitable liver homogenates were analyzed for the same biochemical parameters as the plasma but indices of liver damage. By itself, APAP increased MDA formation and had a significant lowering influence on the levels of GSH and GSSG, the GSH/GSSH ratio, and the activities of GR, GST and GCS both in the plasma and liver. In addition, APAP promoted the leakage of transaminases and lactate dehydrogenase from the liver into the plasma. Without exceptions, a pretreatment with a sulfur-containing compound led to a significant attenuation of the liver injury and the biochemical changes induced by APAP. Within a narrow range of potency differences, HYTAU appeared to be the most protective and TAU the least. The present results suggest that, irrespective of the differences in structural features and in vitro antioxidant properties that may exist among NAC, TAU and HYTAU, these compounds demonstrate equivalent patterns of protection and, to a certain extent, equipotent protective actions against the toxic actions of APAP in the liver when tested in equimolar doses and under the same conditions in an animal model.
authors.affiliation: Department of Pharmaceutical Sciences, St, John's University, College of Pharmacy and Allied Health Professions, 8000 Utopia Parkway, Jamaica, New York 11439, USA. Miteshkumar.Acharya@regeneron.com
authors.forename: Miteshkumar
authors.initials: M
authors.lastname: Acharya
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Lau-Cam
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018712:Analgesics, Non-Narcotic; D000975:Antioxidants; D016166:Free Radical Scavengers; D013654:Taurine; D000082:Acetaminophen; D008315:Malondialdehyde; C003949:hypotaurine; D005982:Glutathione Transferase; D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine
references.citation: J Biol Chem. 1988 Nov 15;263(32):16568-79
references.pmid: 3182803
references.citation: Toxicol Sci. 2003 Oct;75(2):458-67
references.pmid: 12883092
references.citation: Drug Metab Rev. 1995;27(1-2):147-77
references.pmid: 7641574
references.citation: Toxicol Sci. 2004 Aug;80(2):343-9
references.pmid: 15115886
references.citation: Ann Clin Lab Sci. 1997 Sep-Oct;27(5):365-74
references.pmid: 9303176
references.citation: Adv Exp Med Biol. 2006;583:15-24
references.pmid: 17153585
references.citation: J Pineal Res. 2007 Mar;42(2):203-9
references.pmid: 17286753
references.citation: Toxicology. 1982;23(2-3):249-59
references.pmid: 7112597
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12741-5
references.pmid: 11058152
references.citation: J Biol Chem. 2006 Sep 29;281(39):28865-75
references.pmid: 16840778
references.citation: Toxicol Sci. 2003 Nov;76(1):229-36
references.pmid: 12944590
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Jun;280(6):G1274-9
references.pmid: 11352821
references.citation: J Pharmacol Exp Ther. 1990 Dec;255(3):935-41
references.pmid: 2262912
references.citation: Methods Enzymol. 1978;52:302-10
references.pmid: 672633
references.citation: Adv Exp Med Biol. 2009;643:359-68
references.pmid: 19239167
references.citation: Am J Physiol. 1999 Dec;277(6):C1229-38
references.pmid: 10600775
references.citation: Adv Exp Med Biol. 2009;643:491-9
references.pmid: 19239181
references.citation: Proc Natl Acad Sci U S A. 1984 Mar;81(5):1327-31
references.pmid: 6424115
references.citation: Jpn J Pharmacol. 1996 Oct;72(2):175-81
references.pmid: 8912918
references.citation: Toxicology. 1990 Apr 30;61(3):229-39
references.pmid: 2330596
references.citation: Mutagenesis. 2000 Jan;15(1):61-8
references.pmid: 10640532
references.citation: Free Radic Biol Med. 1989;6(6):593-7
references.pmid: 2546864
references.citation: Anal Biochem. 1976 Jul;74(1):214-26
references.pmid: 962076
references.citation: J Surg Res. 2006 Apr;131(2):199-203
references.pmid: 16412470
references.citation: J Biochem Mol Toxicol. 2002;16(5):235-44
references.pmid: 12439865
references.citation: Toxicol Lett. 2004 Dec 30;154(3):165-74
references.pmid: 15501608
references.citation: Anal Biochem. 1990 Feb 1;184(2):193-9
references.pmid: 2327564
references.citation: Physiol Res. 2010;59(2):225-232
references.pmid: 19537930
references.citation: Drug Metab Dispos. 2003 Dec;31(12):1499-506
references.pmid: 14625346
references.citation: J Pharmacol Exp Ther. 1986 Apr;237(1):341-9
references.pmid: 3958971
references.citation: Biochem Pharmacol. 1993 Jun 9;45(11):2289-94
references.pmid: 8517869
references.citation: Biochim Biophys Acta. 1991 Jan 23;1073(1):91-7
references.pmid: 1846756
references.citation: Am J Pathol. 1990 Apr;136(4):787-95
references.pmid: 2158237
references.citation: Adv Exp Med Biol. 2009;643:65-74
references.pmid: 19239137
references.citation: Toxicol Appl Pharmacol. 1981 Sep 15;60(2):229-40
references.pmid: 7281186
references.citation: Free Radic Biol Med. 1995 Sep;19(3):303-10
references.pmid: 7557544
references.citation: Hum Exp Toxicol. 2000 May;19(5):277-83
references.pmid: 10918522
references.citation: J Clin Invest. 1983 Apr;71(4):980-91
references.pmid: 6833497
references.citation: Biochem Pharmacol. 1984 Oct 1;33(19):2989-94
references.pmid: 6148944
references.citation: Biochem Pharmacol. 1984 Oct 1;33(19):2995-3000
references.pmid: 6487352
references.citation: J Biol Chem. 2005 Dec 30;280(52):43150-8
references.pmid: 16227205
references.citation: Scand J Gastroenterol. 1995 Jan;30(1):61-7
references.pmid: 7701253
references.citation: Adv Exp Med Biol. 2000;483:503-22
references.pmid: 11787637
references.citation: J Invest Dermatol. 1993 Jun;100(6):829-33
references.pmid: 8496623
references.citation: J Biol Chem. 2007 Aug 17;282(33):23996-4003
references.pmid: 17573345
references.citation: Toxicol Sci. 2006 Jan;89(1):31-41
references.pmid: 16177235
references.citation: Pharmazie. 2004 Nov;59(11):869-72
references.pmid: 15587589
references.citation: Hepatology. 2010 Jan;51(1):246-54
references.pmid: 19821517
references.citation: J Parasitol. 2001 Apr;87(2):292-9
references.pmid: 11318558
references.citation: J Biol Chem. 1974 Nov 25;249(22):7130-9
references.pmid: 4436300
references.citation: J Pharmacol Exp Ther. 1986 Jul;238(1):54-61
references.pmid: 3723405
references.citation: J Pharmacol Exp Ther. 1985 Mar;232(3):864-72
references.pmid: 3973835
references.citation: Hepatology. 1982 Jan-Feb;2(1):8-12
references.pmid: 7054070
references.citation: Crit Rev Toxicol. 2001 Jan;31(1):55-138
references.pmid: 11215692
references.citation: Eur Respir J. 2004 Apr;23(4):629-36
references.pmid: 15083766
references.citation: J Pharmacol Exp Ther. 2005 Feb;312(2):509-16
references.pmid: 15466245