title: Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.
abstract: Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Jingyao
authors: J
authors: Zhang
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Sidong
authors: S
authors: Song
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Qing
authors: Q
authors: Pang
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Ruiyao
authors: R
authors: Zhang
authors: 1] Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China [2] Departments of Medicine (Division of Molecular and Vascular Biology), Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School. Boston. U.S.A.
authors: Lei
authors: L
authors: Zhou
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Sushun
authors: S
authors: Liu
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Fandi
authors: F
authors: Meng
authors: Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Qifei
authors: Q
authors: Wu
authors: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University; NO.277 Yanta West Road, Xi'an Shaanxi 710061, People's Republic of China.
authors: Chang
authors: C
authors: Liu
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D004198:Disease Susceptibility; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D044403:Receptor, Serotonin, 5-HT2B; D012701:Serotonin / Q000172:deficiency* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D044403:Receptor, Serotonin, 5-HT2B; D012701:Serotonin; C002744:3-nitrotyrosine; D000082:Acetaminophen; D014443:Tyrosine; D019392:Cytochrome P-450 CYP2E1; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D005978:Glutathione
references: Hepatology. 2010 Dec;52(6):2065-76
references: 20949552
references: Mol Pharmacol. 2001 Oct;60(4):847-56
references: 11562448
references: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2945-50
references: 21282654
references: J Pharmacol Exp Ther. 2011 Apr;337(1):110-6
references: 21205919
references: J Pharmacol Exp Ther. 2011 Aug;338(2):492-502
references: 21576378
references: Toxicol Sci. 2011 Aug;122(2):598-605
references: 21572097
references: Drug Metab Rev. 2012 Feb;44(1):88-106
references: 22229890
references: Surgeon. 2012 Apr;10(2):107-13
references: 22119013
references: Hepatology. 2012 Jul;56(1):209-18
references: 22290718
references: Hepatology. 2011 Jan;53(1):253-62
references: 21254175
references: Toxicol Sci. 2002 Jan;65(1):135-50
references: 11752693
references: Pharmacol Toxicol. 2002 Jan;90(1):38-50
references: 12005112
references: Toxicol Sci. 2002 Jun;67(2):322-8
references: 12011492
references: J Pharmacol Exp Ther. 2002 Nov;303(2):468-75
references: 12388625
references: Am J Physiol Gastrointest Liver Physiol. 2003 Jan;284(1):G15-26
references: 12488232
references: Toxicol Appl Pharmacol. 2003 Sep 1;191(2):118-29
references: 12946648
references: Toxicol Sci. 2004 Aug;80(2):343-9
references: 15115886
references: Hepatology. 2004 Nov;40(5):1170-9
references: 15486922
references: J Pharmacol Exp Ther. 1996 Dec;279(3):1470-83
references: 8968373
references: Science. 1997 Apr 4;276(5309):60-6
references: 9082986
references: Brain Behav Immun. 1998 Dec;12(4):249-71
references: 10080856
references: Toxicol Appl Pharmacol. 1999 May 1;156(3):179-86
references: 10222310
references: Cell Growth Differ. 1999 Jun;10(6):397-404
references: 10392901
references: Toxicol Pathol. 2005;33(1):41-51
references: 15805055
references: Drug Metab Rev. 2005;37(3):405-42
references: 16257829
references: Hepatology. 2005 Dec;42(6):1364-72
references: 16317692
references: Toxicol Sci. 2006 Jan;89(1):31-41
references: 16177235
references: Hepatology. 2006 Feb;43(2 Suppl 1):S31-44
references: 16447272
references: Hepatology. 2006 Feb;43(2 Suppl 1):S45-53
references: 16447274
references: Free Radic Biol Med. 2006 Mar 15;40(6):928-39
references: 16540388
references: Science. 2006 Apr 7;312(5770):104-7
references: 16601191
references: J Neurosci. 2006 May 17;26(20):5554-64
references: 16707806
references: FASEB J. 2006 Aug;20(10):1589-98
references: 16873882
references: Am J Pathol. 2006 Sep;169(3):861-76
references: 16936262
references: J Leukoc Biol. 2007 Mar;81(3):599-606
references: 17108054
references: Hepatology. 2007 Feb;45(2):369-76
references: 17256748
references: Hepatology. 2007 Feb;45(2):412-21
references: 17366662
references: Gut. 2007 Jul;56(7):982-90
references: 17185352
references: J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S49-52
references: 17567465
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: Gastroenterology. 2007 Aug;133(2):608-18
references: 17681180
references: Clin Liver Dis. 2007 Aug;11(3):525-48, vi
references: 17723918
references: Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L1045-52
references: 17675372
references: J Hepatol. 2008 Apr;48(4):666-75
references: 18280000
references: J Biol Chem. 2008 May 16;283(20):13565-77
references: 18337250
references: Med Clin North Am. 2008 Jul;92(4):761-94, viii
references: 18570942
references: Swiss Med Wkly. 2008 Jun 28;138(25-26):361-70
references: 18587687
references: Nat Med. 2008 Jul;14(7):756-61
references: 18516052
references: Cancer Res. 2008 Nov 15;68(22):9184-93
references: 19010890
references: Biochem J. 2009 Jan 1;417(1):1-13
references: 19061483
references: Am J Pathol. 2009 Sep;175(3):1056-65
references: 19679878
references: Handb Exp Pharmacol. 2010;(196):369-405
references: 20020268
references: Hepatology. 2010 Feb;51(2):615-20
references: 19839004
references: Free Radic Res. 2010 Mar;44(3):340-55
references: 20166895
references: Hepatology. 2010 Apr;51(4):1244-54
references: 20099302
references: Dig Dis Sci. 2012 Nov;57(11):2856-62
references: 22615020
references: Cancer Lett. 2013 Apr 30;331(1):105-14
references: 23262037
references: J Hepatol. 2013 Sep;59(3):495-503
references: 23665281
references: World J Gastroenterol. 2014 Feb 14;20(6):1614-22
references: 24587639
references: Pharmacol Toxicol. 2001 Mar;88(3):135-41
references: 11245408
references: Toxicol Sci. 2001 Aug;62(2):212-20
references: 11452133