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Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepatotoxicity.

ABSTRACT: Acetaminophen (APAP) overdose is the most frequent cause of liver injury and acute liver failure in many western countries. The mechanism of APAP-induced hepatocyte necrosis has been investigated extensively. The formation of a reactive metabolite and its binding to cellular proteins was initially thought to be responsible for cell death. A competing hypothesis was introduced that questioned the relevance of protein binding and instead suggested that P450-derived oxidant stress and lipid peroxidation causes APAP-induced liver injury. However, work over the last 15 years has reconciled some of these apparent contradictory hypotheses. This review summarizes the present state of knowledge on the role of reactive oxygen species (ROS) in APAP hepatotoxicity. Detailed investigations into the sources and relevance of the oxidant stress have clearly shown the critical role of the electron transport chain of mitochondria as main source of the oxidant stress. Other potential sources of ROS such as cytochrome P450 enzymes or NADPH oxidase on phagocytes are of limited relevance. The mitochondria-derived superoxide and peroxynitrite formation is initiated by the binding of the reactive metabolite to mitochondrial proteins and the amplification by mitogen activated protein kinases. The consequences of this oxidant stress are the opening of the mitochondrial membrane permeability transition pore with cessation of ATP synthesis, nuclear DNA fragmentation and ultimately cell necrosis. Lipid peroxidation is not a relevant mechanism of cell death but can be a marker of ROS formation. These mechanistic insights suggest that targeting mitochondrial oxidant stress is a promising therapeutic option for APAP hepatotoxicity.

SUBMITTER: Jaeschke H

PROVIDER: S-EPMC5903282 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepatotoxicity.

Jaeschke Hartmut H Ramachandran Anup A

Reactive oxygen species (Apex, N.C.) 20180501 15

Acetaminophen (APAP) overdose is the most frequent cause of liver injury and acute liver failure in many western countries. The mechanism of APAP-induced hepatocyte necrosis has been investigated extensively. The formation of a reactive metabolite and its binding to cellular proteins was initially thought to be responsible for cell death. A competing hypothesis was introduced that questioned the relevance of protein binding and instead suggested that P450-derived oxidant stress and lipid peroxid ...[more]

PMID: 29682614

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Project description:ObjectiveHemolysis, occurring during cardiopulmonary bypass, is associated with lipid peroxidation and postoperative acute kidney injury. Acetaminophen inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced acute kidney injury. This pilot study tests the hypothesis that acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass.DesignSingle-center prospective randomized double-blinded study.SettingUniversity-affiliated pediatric hospital.PatientsThirty children undergoing elective surgical correction of a congenital heart defect.InterventionsPatients were randomized to acetaminophen (OFIRMEV [acetaminophen] injection; Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for four doses starting before the onset of cardiopulmonary bypass.Measurement and main resultsMarkers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes), and acute kidney injury were measured throughout the perioperative period. Cardiopulmonary bypass was associated with a significant increase in free hemoglobin (from a prebypass level of 9.8 ± 6.2 mg/dL to a peak of 201.5 ± 42.6 mg/dL postbypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. Acetaminophen attenuated the increase in plasma isofurans compared with placebo (p = 0.02 for effect of study drug). There was no significant effect of acetaminophen on plasma F2-isoprostanes or urinary makers of lipid peroxidation. Acetaminophen did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin, or prevalence of acute kidney injury.ConclusionCardiopulmonary bypass in children is associated with hemolysis and lipid peroxidation. Acetaminophen attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients undergoing cardiopulmonary bypass.

Project description:Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Project description:BackgroundCardiopulmonary bypass (CPB) lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.Methods and resultsIn a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 ± 0.6 ?g/mL (78.9 ± 3.9 ?M) and 8.7 ± 0.3 ?g/mL (57.6 ± 2.0 ?M), respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05), and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03). Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation.ConclusionsIntravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.Trial registrationClinicalTrials.gov NCT01366976.

Project description:Herein we report an investigation of the efficacy of pyridine and pyrimidine analogs of acetaminophen (ApAP) as peroxyl radical-trapping antioxidants and inhibitors of enzyme-catalyzed lipid peroxidation by cyclooxygenases (COX) and lipoxygenases (LOX). In inhibited autoxidations we find that ApAP, the common analgesic and antipyretic agent, is a very good antioxidant with a rate constant for reaction with peroxyl radicals (k(inh) = 5 x 10(5) M(-1) s(-1)) that is higher than many widely-used phenolic antioxidants, such as the ubiquitous butylated hydroxytoluene (BHT). This reactivity is reduced substantially upon incorporation of nitrogen into the phenolic ring, owing to an increase in the O-H bond dissociation enthalpy of pyridinols and pyrimidinols with respect to phenols. Incorporation of nitrogen into the phenolic ring of ApAP was also found to decrease its efficacy as an inhibitor of prostaglandin biosynthesis by ovine COX-1 (oCOX-1). This is explained on the basis of an increase in its oxidation potential and its reduced reactivity as a reducing co-substrate of the peroxidase protoporphyrin. In contrast, the efficacy of ApAP as an inhibitor of lipid hydroperoxide biosynthesis by soybean LOX-1 (sLOX-1) increased upon incorporation of nitrogen into the ring, suggesting a different mechanism of inhibition dependent on the acidity of the phenolic O-H which may involve chelation of the catalytic non-heme iron atom. The greater stability of the 3-pyridinols and 5-pyrimidinols to air oxidation as compared to phenols allowed us to evaluate some electron-rich pyridinols and pyrimidinols as inhibitors of oCOX-1 and sLOX-1. While the pyridinols had the best combination of activities as antioxidants and inhibitors of oCOX-1 and sLOX-1, they were found to be more toxic than ApAP in preliminary assays in human hepatocellular carcinoma (HepG2) cell culture. The pyrimidinols, however, were up to 17-fold more reactive to peroxyl radicals and up to 25-fold better inhibitors of prostaglandin biosynthesis than ApAP, with similar cytotoxicities to HepG2 cells at high levels of exposure.

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Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepatotoxicity.

Publications

Oxidant Stress and Lipid Peroxidation in Acetaminophen Hepatotoxicity.

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