In mitochondria undergoing the MPT, however, matrix swelling and outer membrane rupture causes release of mitochondrial cytochrome c , which activates caspases in the cytosol to cause apoptosis Bradham et al.
Drugs cause the MPT through diverse mechanisms. Some compounds, such as ROS Nieminen et al. The most frequent mechanism of cytolytic hepatitis is cytochrome Pdependent formation of reactive metabolites that cause direct toxicity or immune reactions. Covalent binding of reactive metabolites to hepatic proteins can also trigger an immune response. All 3 events trigger the MPT to cause death of target cells Bradham et al.
In summary, several mechanisms initiate liver cell damage and aggravate ongoing injury processes. Mitochondria are prominent targets for the hepatotoxicity of many drugs. Dysfunction of these vital cell organelles results in impairment of energy metabolism and an intracellular oxidant stress with excessive formation of reactive oxygen species and peroxynitrite.
In addition to mitochondria, induction of cytochrome P isoenzymes such as CYP2E1 also promote oxidant stress and cell injury. Once hepatocellular function is impaired, accumulation of bile acids causes additional stress and cytotoxicity. Cell injury, gut-derived endotoxin or a combination of both also activate Kupffer cells and recruit neutrophils into the liver. Although responsible for removal of cell debris and part of the host-defense system, under certain circumstances these inflammatory cells initiate additional liver injury.
However, cell injury and death is not only determined by the nature and dose of a particular drug but also by factors such as an individual's gene expression profile, antioxidant status, and capacity for regeneration. Because of the many direct and indirect mechanisms of drug-induced cell injury in the liver, hepatotoxicity remains a major reason for drug withdrawal from pharmaceutical development and clinical use. Bile acid-induced hepatocyte apoptosis. Bile acids are normally secreted rapidly from hepatocytes by transporters located in the canalicular membrane.
In cholestasis, secretion is impaired, resulting in elevated concentrations of toxic bile acids TBA within hepatocytes. At pathophysiologic concentrations, toxic bile acids trigger translocation of intracellular Fas bearing vesicles to the plasma membrane where they self-aggregate in the absence of ligand. Activated Fas receptor complexes on the plasma membrane then cause caspase 8 activation and an apoptotic cascade. Mechanisms of neutrophil-induced liver injury.
In addition, cytokines activate expression of adhesion molecules on endothelial cells EC and hepatocytes PC. If primed neutrophils receive a chemotactic signal from the parenchyma, they will transmigrate and adhere to hepatocytes. This leads to the final activation of neutrophil with degranulation protease release and adherence-dependent oxidant stress, which causes cell necrosis.
Mediators generated during cell injury, such as lipid peroxidation products LPO and chemokines, become chemotactic signals for further neutrophil activation and transmigration. Role of cytochrome PE1 in oxidative stress after ethanol. Ethanol increases levels of CYP2E1, largely by a posttranscriptional mechanism involving stabilization against degradation.
CYP2E1, a loosely coupled enzyme, generates reactive oxygen species such as superoxide radical and hydrogen peroxide during its catalytic cycle.
In the presence of iron, which is increased after ethanol treatment, more powerful oxidants including hydroxyl radical, ferryl species, and 1-hydroxyethyl radical are produced. These various oxidants can promote toxicity by protein oxidation and enzyme inactivation and by damage to cell membranes via lipid peroxidation and production of reactive lipid aldehydes, such as malondialdehyde and 4-hydroxynonenal.
Mitochondria appear to be among the critical cellular organelles damaged by CYP2E1-derived oxidants. A decrease of mitochondrial membrane potential and perhaps the mitochondrial membrane permeability transition causes release of proapoptotic factors resulting in apoptosis.
Some CYP2E1-derived reactive oxygen species, e. Postulated mechanism of acetaminophen APAP -induced hepatotoxicity. Hepatocytes, Kupffer cells, and endothelial cells all participate in the production of reactive nitrogen and oxygen species. The relative levels of nitric oxide NO and superoxide O 2 - determine whether the mechanism of hepatic necrosis is dependent on protein nitrosylation or lipid peroxidation.
To whom correspondence should be addressed. Fax: E-mail: lemaster med. Bai, J. Adenovirus-mediated overexpression of catalase in the cytosolic or mitochondrial compartment protects against cytochrome PE1-dependent toxicity in HepG2 cells.
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Chosay, J. Neutrophil margination and extravasation in sinusoids and venules of the liver during endotoxin-induced injury. Cohen, S. Selective protein covalent binding and target organ toxicity.
Curzio, M. Chemotactic activity of the lipid peroxidation product 4-hydroxynonenal and homologous hydroxyalkenals. Hoppe Seyler , — Dai, Y. Cytotoxicity of acetaminophen in human cytochrome PE1-transfected HepG2 cells.
Exp Ther. Stable transfection of human cytochrome PE1 in HepG2 cells: Characterization of catalytic activities and production of reactive oxygen intermediates. Biochemistry 32 , — Deschamps, D. Hepatology 19 , — Inhibition by salicylic acid of the activation and thus oxidation of long-chain fatty acids.
Possible role in the development of Reye's syndrome. Dianzani, M. Lipid peroxidation in ethanol poisoning: A critical reconsideration. Alcohol 20 , — Essani, N. Transcriptional activation of vascular cell adhesion molecule-1 gene in vivo and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock. A, Fisher, M. Cytokine-induced hepatic intercellular adhesion molecule-1 ICAM-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure.
Hepatology 21 , — Faubion, W. Death receptors in liver biology and pathobiology. Hepatology 29 , 1 —4. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. Feldmann, G. Opening of the mitochondrial permeability transition pore causes matrix expansion and outer membrane rupture in Fas-mediated hepatic apoptosis in mice. Hepatology 31 , — Friedman, S. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.
Fromenty, B. Fulda, S. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. Gardner, C. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology 27 , — Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug. Goldin, R. Role of macrophages in acetaminophen paracetamol -induced hepatotoxicity. Green, D. Apoptotic pathways: The roads to ruin. Cell 94 , — Grimbert, S. Decreased mitochondrial oxidation of fatty acids in pregnant mice: Possible relevance to development of acute fatty liver of pregnancy.
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Haouzi, D. Cytochrome Pgenerated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes. Hepatology 32 , — Hatano, E. The mitochondrial permeability transition augments Fas-induced apoptosis in mouse hepatocytes. Hinson, J. Western blot analysis for nitrotyrosine protein adducts in livers of saline-treated and acetaminophen-treated mice. Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice.
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Hepatology 29 , — Mechanisms of neutrophil-induced parenchymal cell injury. Mechanisms of inflammatory liver injury: Adhesion molecules and cytotoxicity of neutrophils. Kamiyama, T. Role of lipid peroxidation in acetaminophen-induced hepatotoxicity: Comparison with carbon tetrachloride. Kassahun, K. In vivo formation of the thiol conjugates of reactive metabolites of 4-ene VPA and its analog 4-pentenoic acid.
Drug Metab. Kesterson, J. The hepatotoxicity of valproic acid and its metabolites in rats. Toxicologic, biochemical, and histopathologic studies.
Hepatology 4 , — Knight, T. Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: Role of mitochondrial oxidant stress. Koop, D. Oxidative and reductive metabolism by cytochrome PE1.
Labbe, G. Laskin, D. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Role of macrophages and inflammatory mediators in chemically induced toxicity. Toxicology , — Introduction Liver plays a key role in detoxifying harmful substances that you may eat, drink, inhale or rub on your skin. Located in the right upper quadrant of the abdominal cavity, resting just below the diaphragm.
The liver lies to the right of the stomach and overlies the gallbladder. Factors Influencing Susceptibility 1. Toxicokinetic factors : accumulation of high concentrations of a xenobiotic Well-perfused organs or tissues — those that receive strong blood flow — can also readily accumulate blood-borne toxicants. These considerations are especially important for the liver and kidneys — which as major excretory organs necessarily receive a high blood flow while also strongly expressing many xenobiotic transporters.
Factors Influencing Susceptibility 2. Metabolic fate of a chemical: high-level expression of xenobiotic-metabolizing enzymes 7. Mechanistic Toxicology The molecular basis of how chemicals disrupt biological targets, Urs A. This promotes further liver damage. Acetaminophen 3D structure overdose is the most common cause of drug induced liver disease They promote glycogen storage in liver.
The classical effect of prolonged use both in adult and pediatric population is steatosis. Complications:- Except for gallstone disease and some viral infections such as Hepatitis A and infectious mononucleosis, most liver diseases are managed and not cured. Liver disease can progress to cirrhosis and liver failure. Associated complications may include increased risk of bleeding and infection, malnutrition and weight loss, and decreased cognitive function.
Some liver diseases are associated with an increased risk for developing liver cancer People with severe symptoms are likely to receive supportive therapy in the hospital, including intravenous fluids and medication to relieve nausea and vomiting.
When liver function is severely impaired, a liver transplant may be the only option for some people Ultrastructural Images Images contd. Acetaminophen Hepatotoxicity Web 6 Oct.
Acetaminophen Metabolism Source: "Acetaminophen Metabolism. However their chances of hepatotoxicity is lower unclear - Peak Serum concentrations of acute overdose may be delayed by as much as 4 hours Acetaminohen Structure: Harrison, Kari.
Adults Source: Kociancic, Todd. Pharmacotherapy Publications Inc, Children vs. Schaefer, Jeffrey P. Jeffrey P Schaefer, 14 Oct. O'Malley, Gerald F. Thomson Reuters Healthcare Inc. Neonates, Patients with altered mental status, GI bleed, repeat vomiting etc.
Mangafodipir prevents liver injury induced by acetaminophen in the mouse. Hepatocyte necrosis is consecutive … Expand. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Role of macrophages and inflammatory mediators in chemically induced toxicity.
View 2 excerpts, references background. Cytochrome P—generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes.
View 5 excerpts, references background. View 1 excerpt, references background. Reactive oxygen and mechanisms of inflammatory liver injury. Journal of gastroenterology and hepatology. View 4 excerpts, references background. Mechanisms of inflammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicology and applied pharmacology. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity.
View 8 excerpts, references background. Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide. American journal of physiology. Gastrointestinal and liver physiology.
View 1 excerpt, references results. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. The Journal of clinical investigation.
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