Acetaminophen Research Today is a free monthly online journal that collates and summarizes the latest research about Acetaminophen, including details on paracetamol, pain relief, side effects, toxicity. | ||||||
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The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity.Ramachandran A, Lebofsky M, Weinman SA, Jaeschke H Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160, USA. Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after APAP overdose. Treatment of C57Bl/6J wild type animals with 200mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870±180U/L) and centrilobular necrosis at 6h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to-GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK. SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation. Conclusions: the impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and more necrosis. Published 1 March 2011 in Toxicol Appl Pharmacol, 251(3): 226-33. Articles on Acetaminophen published 1 March 2011: Secretory phospholipase A₂-mediated progression of hepatotoxicity initiated by acetaminophen is exacerbated in the absence of hepatic COX-2. Toxicol Appl Pharmacol, 251(3): 173-80. We have previously reported that among the other death proteins, hepatic secretory phospholipase A₂ (sPLA₂) is a leading mediator of progression of liver injury initiated by CCl₄ in rats. The aim of our present study was to test the hypothesis that increased hepatic sPLA₂ released after acetaminophen (APAP) challenge mediates progression of liver injury in wild type (WT) and COX-2 knockout (KO) mice. COX-2 WT and KO mice were administered a normally non lethal dose (400 mg/kg) of ... [Abstract] [Full-text] Articles on Acetaminophen published 14 February 2011: Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth, 106(3): 292-7. Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse ... [Abstract] [Full-text] Articles on Acetaminophen published 31 January 2011: Associations of aspirin, nonsteroidal anti-inflammatory drug and paracetamol use with PSA-detected prostate cancer: findings from a large, population-based, case-control study (the ProtecT study). Int J Cancer, 128(6): 1442-8. Evidence from laboratory studies suggests that chronic inflammation plays an important role in prostate cancer aetiology. This has resulted in speculation that nonsteroidal anti-inflammatory drugs may protect against prostate cancer development. We analysed data from a cross-sectional case-control study (n(cases) = 1,016; n(controls) = 5,043), nested within a UK-wide population-based study that used prostate specific antigen (PSA) testing for identification of asymptomatic prostate cancers, to ... [Abstract] [Full-text] Associations of aspirin, nonsteroidal anti-inflammatory drug and paracetamol use with PSA-detected prostate cancer: findings from a large, population-based, case-control study (the ProtecT study). Int J Cancer, 128(6): 1442-8. Evidence from laboratory studies suggests that chronic inflammation plays an important role in prostate cancer aetiology. This has resulted in speculation that nonsteroidal anti-inflammatory drugs may protect against prostate cancer development. We analysed data from a cross-sectional case-control study (n(cases) = 1,016; n(controls) = 5,043), nested within a UK-wide population-based study that used prostate specific antigen (PSA) testing for identification of asymptomatic prostate cancers, to ... [Abstract] [Full-text] Articles on Acetaminophen published 18 January 2011: Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. Am J Respir Crit Care Med, 183(2): 171-8. The role of acetaminophen and geohelminth infection on the incidence of wheeze and eczema: a longitudinal birth-cohort study. Am J Respir Crit Care Med, 183(2): 165-70. Articles on Acetaminophen published 3 January 2011: Application of toxicogenomics in hepatic systems toxicology for risk assessment: acetaminophen as a case study. Toxicol Appl Pharmacol, 250(2): 96-107. Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as ... [Abstract] [Full-text] Application of toxicogenomics in hepatic systems toxicology for risk assessment: acetaminophen as a case study. Toxicol Appl Pharmacol, 250(2): 96-107. Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as ... [Abstract] [Full-text] © 2004-2011 Acetaminophen Research Today. All Rights Reserved. |
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