Mechanisms of Acetaminophen-Induced Liver Necrosis
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TLDR
The mechanism occurs by a complex sequence of events including: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathion with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; andAbstract:
Although considered safe at therapeutic doses, at higher doses, acetaminophen produces a centrilobular hepatic necrosis that can be fatal. Acetaminophen poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. The mechanism occurs by a complex sequence of events. These events include: (1) CYP metabolism to a reactive metabolite which depletes glutathione and covalently binds to proteins; (2) loss of glutathione with an increased formation of reactive oxygen and nitrogen species in hepatocytes undergoing necrotic changes; (3) increased oxidative stress, associated with alterations in calcium homeostasis and initiation of signal transduction responses, causing mitochondrial permeability transition; (4) mitochondrial permeability transition occurring with additional oxidative stress, loss of mitochondrial membrane potential, and loss of the ability of the mitochondria to synthesize ATP; and (5) loss of ATP which leads to necrosis. Associated with these essential events there appear to be a number of inflammatory mediators such as certain cytokines and chemokines that can modify the toxicity. Some have been shown to alter oxidative stress, but the relationship of these modulators to other critical mechanistic events has not been well delineated. In addition, existing data support the involvement of cytokines, chemokines, and growth factors in the initiation of regenerative processes leading to the reestablishment of hepatic structure and function.read more
Citations
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Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing
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Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis
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Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver
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The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology
Paolo Bernardi,Andrea Rasola,Andrea Rasola,Andrea Rasola,Michael Forte,Giovanna Lippe,Giovanna Lippe,Giovanna Lippe +7 more
TL;DR: Structural and functional features of F-ATP synthases are discussed that may provide clues to its transition from an energy-conserving into anEnergy-dissipating device as well as recent advances on signal transduction to the PTP and on its role in cellular pathophysiology.
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Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.
Ryan E. Morgan,Michael Trauner,Carlo van Staden,Paul H. Lee,Bharath Ramachandran,Michael Eschenberg,Cynthia A. Afshari,Charles W. Qualls,Ruth Lightfoot-Dunn,Hisham K. Hamadeh +9 more
TL;DR: In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEp function and liver injury, and suggest a relatively strong association between the pharmacological interference with bile salt export pump function and human hepatotoxicity.
References
More filters
Journal ArticleDOI
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.
J. S. Beckman,Willem H. Koppenol +1 more
TL;DR: The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks.
Journal Article
Liver regeneration : Frontiers in medicine: Regeneration
TL;DR: This review attempts to integrate the findings of the last three decades and looks toward clues as to the nature of the causes that trigger this fascinating organ and cellular response.
Journal ArticleDOI
Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death
Christopher P. Baines,Robert A. Kaiser,Nicole H. Purcell,N. Scott Blair,Hanna Osinska,Michael Hambleton,Eric W. Brunskill,M. Richard Sayen,Roberta A. Gottlieb,Gerald W. Dorn,Jeffrey Robbins,Jeffery D. Molkentin +11 more
TL;DR: Cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.
Journal ArticleDOI
Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States
George Ostapowicz,Robert J. Fontana,Frank V. Schioødt,Anne M. Larson,Timothy J. Davern,Steven Han,Timothy M. McCashland,A. Obaid Shakil,J. Eileen Hay,Linda S. Hynan,Jeffrey S. Crippin,Andres T. Blei,Grace Samuel,Joan S. Reisch,William M. Lee,Raj Santyanarayana,Cary Caldwell,Lawton Shick,Nathan M. Bass,Smita Rouillard,E Atillasoy,Steven L. Flamm,Kent G. Benner,Hugo R. Rosen,Paul Martin,Rise Stribling,Eugene R. Schiff,Maria Torres,Victor J. Navarro,Brendan M. McGuire,Raymond T. Chung,Diane R. Abraczinskas,Jules L. Dienstag +32 more
TL;DR: The primary aim was to compare presenting clinical features and liver transplantation in patients with acute liver failure related to acetaminophen hepatotoxicity, other drugs, indeterminate factors, and other causes.
Journal ArticleDOI
Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.
Anne M. Larson,Julie Polson,Robert J. Fontana,Timothy J. Davern,Ezmina Lalani,Linda S. Hynan,Joan S. Reisch,Frank V. Schiødt,George Ostapowicz,A. Obaid Shakil,William M. Lee +10 more
TL;DR: In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States, and education of patients, physicians, and pharmacies to limit high‐risk use settings is recommended.