Mechanism of action of the antifibrogenic compound gliotoxin in rat liver cells

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
James G OrrMatthew C Wright

Abstract

Gliotoxin has been shown to promote a reversal of liver fibrosis in an animal model of the disease although its mechanism of action in the liver is poorly defined. The effects of gliotoxin on activated hepatic stellate cells (HSCs) and hepatocytes have therefore been examined. Addition of gliotoxin (1.5 microM) to culture-activated HSCs resulted in its rapid accumulation, resulting in increased levels of glutathione and apoptosis without any evidence of oxidative stress. In contrast, although hepatocytes also rapidly sequestered gliotoxin, cell death only occurred at high (50-microM) concentrations of gliotoxin and by necrosis. At high concentrations, gliotoxin was metabolized by hepatocytes to a reduced (dithiol) metabolite and glutathione was rapidly oxidized. Fluorescent dye loading experiments showed that gliotoxin caused oxidative stress in hepatocytes. Antioxidants--but not thiol redox active compounds--inhibited both oxidative stress and necrosis in hepatocytes. In contrast, HSC apoptosis was not affected by antioxidants but was potently abrogated by thiol redox active compounds. The adenine nucleotide transporter (ANT) is implicated in mitochondrial-dependent apoptosis. HSCs expressed predominantly nonliver ANT isoform ...Continue Reading

References

Oct 15, 1992·The Biochemical Journal·A R FreedmanG E Griffin
Aug 1, 1991·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·D SorrentinoC M Miller
Apr 1, 1994·Toxicon : Official Journal of the International Society on Toxinology·P WaringA Mullbacher
Apr 1, 1996·The Journal of Experimental Medicine·H L PahlP A Baeuerle
Dec 1, 1996·General Pharmacology·P Waring, J Beaver
Oct 31, 1998·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·E M WebberN Fausto
Jan 23, 1999·Oncogene·E C LaCasseA E MacKenzie
Mar 27, 1999·Biochemical and Biophysical Research Communications·A Rodriguez-Ariza, A J Paine
Jan 25, 2000·American Journal of Physiology. Gastrointestinal and Liver Physiology·J PlümpeC Trautwein
Jan 25, 2000·The Journal of Biological Chemistry·S L Friedman
Aug 1, 2000·American Journal of Physiology. Gastrointestinal and Liver Physiology·M J Arthur
Aug 29, 2000·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·W X DingC N Ong
Sep 6, 2000·Trends in Biochemical Sciences·N D Perkins
Oct 12, 2000·Cell Biology International·W Jakubowski, G Bartosz
Mar 7, 2001·Bioorganic & Medicinal Chemistry Letters·P H BernardoP Waring
Jun 8, 2001·Trends in Pharmacological Sciences·S B Bratton, G M Cohen
Aug 2, 2001·Biochemical and Biophysical Research Communications·W X DingC N Ong
Oct 5, 2001·Seminars in Liver Disease·R Bataller, D A Brenner
May 7, 2002·Frontiers in Bioscience : a Journal and Virtual Library·Leonie BeljaarsKlaas Poelstra
May 23, 2002·Biochimie·Andrew P HalestrapSamantha J Clarke
Nov 26, 2002·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Young-Soo KimDavid A Brenner
May 6, 2003·Biochemical and Biophysical Research Communications·Jae-Sung KimJohn J Lemasters
Aug 20, 2003·Digestive Diseases and Sciences·Roy DekelRan Oren

❮ Previous
Next ❯

Citations

Sep 10, 2005·Apoptosis : an International Journal on Programmed Cell Death·A M ElsharkawyD A Mann
Feb 11, 2005·Current Gastroenterology Reports·T Barry Kelleher, Nezam Afdhal
Aug 12, 2009·Hepatology International·Angela DouglassMatthew C Wright
Mar 16, 2011·Chemical Reviews·Jonas J Forsman, Reko Leino
Dec 1, 2007·Nature Reviews. Drug Discovery·Michael P MannsMichael Houghton
May 9, 2012·International Journal of Hepatology·Jayashree Bagchi ChakrabortyMeagan J Walsh
May 13, 2009·Comparative Hepatology·Carylyn J MarekMatthew C Wright
Aug 30, 2007·Critical Reviews in Therapeutic Drug Carrier Systems·Kun Cheng, Ram I Mahato
Sep 28, 2013·Acta Medica (Hradec Králové)·Lenka BittnerováJirí Kanta
Sep 3, 2009·Expert Opinion on Biological Therapy·Ping-Fang Hu, Wei-Fen Xie
Jan 19, 2016·Frontiers in Pharmacology·Ralf Weiskirchen
May 8, 2013·The Journal of Surgical Research·Mohamed S NoormohamedSteven A White
Nov 6, 2008·Clinics in Liver Disease·Roben G GielingDerek A Mann
Dec 14, 2005·Alcoholism, Clinical and Experimental Research·Sören V Siegmund, David A Brenner
Apr 21, 2005·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Sören V SiegmundRobert F Schwabe
Feb 2, 2006·Liver International : Official Journal of the International Association for the Study of the Liver·Werner I HagensKlaas Poelstra
Sep 11, 2012·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Juan E PucheScott L Friedman
Apr 5, 2013·Liver International : Official Journal of the International Association for the Study of the Liver·Kari N Nejak-BowenGeorge K Michalopoulos
Mar 22, 2005·Journal of Hepatology·Massimo PinzaniStefano Colagrande
Jun 6, 2006·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·A FedericoC Loguercio
Sep 20, 2005·Journal of Hepatology·Svenja NeyzenRalf Weiskirchen
May 6, 2016·Oxidative Medicine and Cellular Longevity·Stanislava VrankováJosef Zicha
Apr 27, 2010·The Journal of Steroid Biochemistry and Molecular Biology·Karen WallaceMatthew C Wright
Apr 9, 2008·Journal of Hepatology·Angela DouglassMatthew C Wright
Feb 19, 2008·Journal of Hepatology·Martha R WatsonFiona Oakley
Jun 10, 2016·Stem Cells Translational Medicine·Marina HirataAkihito Yamamoto
Mar 2, 2006·Digestive Diseases·Soren V SiegmundDavid A Brenner
Dec 14, 2007·The Journal of Pharmacology and Experimental Therapeutics·W I HagensK Poelstra
Mar 13, 2008·The Biochemical Journal·Karen WallaceMatthew C Wright
Feb 15, 2020·New Zealand Veterinary Journal·T W Jordan
Nov 1, 2006·Biochemical Society Transactions·M C Wright
May 24, 2017·Amino Acids·Liuqin HeYulong Yin
Aug 11, 2020·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Tarek M AbdelghanyMatthew C Wright
Oct 28, 2020·Proceedings of the National Academy of Sciences of the United States of America·Roger Flores-CostaJoan Clària

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis