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acetaminophen and liver

A D B Vliegenthart, R A Kimmitt, J H Seymour, N Z Homer, J I Clarke, M Eddleston, A Gray, D M Wood, P I Dargan, J G Cooper, D J Antoine, D J Webb, S C Lewis, D N Bateman, J W Dear
: Acetaminophen (paracetamol-APAP) is the commonest cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analysed from discovery (N=116) and validation (N=150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI...
October 22, 2016: Clinical Pharmacology and Therapeutics
Robim M Rodrigues, Olivier Govaere, Tania Roskams, Tamara Vanhaecke, Vera Rogiers, Joery De Kock
This data set is composed of transcriptomics analyses of (i) liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF) and (ii) hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC). Data from primary human hepatocytes was also added to the data set "Open TG-GATEs: a large-scale toxicogenomics database" (Igarashi et al...
June 2016: Data in Brief
Harriet Gaskell, Parveen Sharma, Helen E Colley, Craig Murdoch, Dominic P Williams, Steven D Webb
More predictive in vitro liver models are a critical requirement for preclinical screening of compounds demonstrating hepatotoxic liability. 3D liver spheroids have been shown to have an enhanced functional lifespan compared to 2D monocultures; however a detailed characterisation of spatiotemporal function and structure of spheroids still needs further attention before widespread use in industry. We have developed and characterized the structure and function of a 3D liver spheroid model formed from C3A hepatoma cells...
June 1, 2016: Toxicology Research
Kuo Du, Anup Ramachandran, Hartmut Jaeschke
Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death...
October 4, 2016: Redox Biology
Chun Pang, Liang Shi, Yuchen Sheng, Zhiyong Zheng, Hai Wei, Zhengtao Wang, Lili Ji
Caffeic acid (CA) is a natural compound abundant in fruits, coffee and plants. This study aims to investigate the involved mechanism of the therapeutic detoxification of CA against acetaminophen (APAP)-induced hepatotoxicity. CA (10, 30 mg/kg) was orally given to mice at 1 h after mice were pre-administrated with APAP (300 mg/kg). The therapeutic detoxification of CA against APAP-induced hepatotoxicity was observed by detecting serum aminotransferases, liver malondialdehyde (MDA) amount and liver histological evaluation in vivo...
October 6, 2016: Chemico-biological Interactions
Dushani L Palliyaguru, Dionysios V Chartoumpekis, Nobunao Wakabayashi, John J Skoko, Yoko Yagishita, Shivendra V Singh, Thomas W Kensler
Small molecules of plant origin offer presumptively safe opportunities to prevent carcinogenesis, mutagenesis and other forms of toxicity in humans. However, the mechanisms of action of such plant-based agents remain largely unknown. In recent years the stress responsive transcription factor Nrf2 has been validated as a target for disease chemoprevention. Withania somnifera (WS) is a herb used in Ayurveda (an ancient form of medicine in South Asia). In the recent past, withanolides isolated from WS, such as Withaferin A (WA) have been demonstrated to be preventive and therapeutic against multiple diseases in experimental models...
October 4, 2016: Free Radical Biology & Medicine
Annelies Paridaens, Sarah Raevens, Isabelle Colle, Eliene Bogaerts, Yves-Paul Vandewynckel, Xavier Verhelst, Anne Hoorens, Leo A van Grunsven, Hans Van Vlierberghe, Anja Geerts, Lindsey Devisscher
BACKGROUND & AIMS: Acetaminophen overdose in mice is characterized by hepatocyte endoplasmic reticulum stress, which activates the unfolded protein response, and centrilobular hepatocyte death. We aimed at investigating the therapeutic potential of tauroursodeoxycholic acid, a hydrophilic bile acid known to have anti-apoptotic and endoplasmic reticulum stress reducing capacities, in experimental acute liver injury induced by acetaminophen overdose. METHODS: Mice were injected with 300 mg/kg acetaminophen, two hours prior to receiving tauroursodeoxycholic acid, N-acetylcysteine or a combination therapy, and were euthanized 24 hours later...
October 5, 2016: Liver International: Official Journal of the International Association for the Study of the Liver
Zongmei Wen, Zhen Lei, Lu Yao, Ping Jiang, Tao Gu, Feng Ren, Yan Liu, Chunyan Gou, Xiuhui Li, Tao Wen
Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production...
2016: Cell Death & Disease
Yakov M Koen, Ke Liu, Heather Shinogle, Todd D Williams, Robert P Hanzlik
The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in APAP metabolism and toxicity, we synthesized 12 acyl side chain homologues of acetaminophen (APAP) and its 3'-regioisomer (AMAP), including the respective N-(4-pentynoyl) analogues PYPAP and PYMAP. Rat hepatocytes converted APAP, AMAP, PYPAP, and PYMAP extensively to O-glucuronide and O-sulfate conjugates in varying proportions, whereas glutathione or cysteine conjugates were observed only for APAP and PYPAP...
October 13, 2016: Chemical Research in Toxicology
Kai Yuan, Xue Zhang, Lei Lv, Jiwei Zhang, Wei Liang, Peng Wang
Treatment of acetaminophen (APAP) in overdose can cause a potentially serious and fatal liver injury. MicroRNA-155 (miR-155), a multifunctional microRNA, is known to mediate inflammatory responses via regulating various target genes. In this study, we aimed to study the role of miR-155 in APAP-induced liver injury, using miR-155-/- mice and miR-155 in vivo intervention. We noted that miR-155 expression was significantly increased in liver and blood after APAP treatment. Knockout of miR-155 deteriorated APAP-induced liver damage, with the elevated serum levels of AST and ALT...
September 24, 2016: International Immunopharmacology
Keisuke Goda, Tadakazu Takahashi, Akio Kobayashi, Toshiyuki Shoda, Hideyuki Kuno, Shoichiro Sugai
Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown...
2016: Journal of Toxicological Sciences
Dean W Roberts, William M Lee, Jack A Hinson, Shasha Bai, Christopher J Swearingen, R Todd Stravitz, Adrian Reuben, Lynda Letzig, Pippa M Simpson, Jody Rule, Robert J Fontana, Daniel Ganger, K Rajender Reddy, Iris Liou, Oren Fix, Laura P James
BACKGROUND & AIMS: A rapid, reliable point-of-care assay to detect acetaminophen protein adducts in serum of patients with acute liver injury could improve diagnosis and management. AcetaSTAT is a competitive immunoassay used to measure acetaminophen protein adducts formed by toxic metabolites in serum samples from patients. We compared the accuracy of AcetaSTAT vs high-pressure liquid chromatography with electrochemical detection (HPLC-EC, a sensitive and specific quantitative analytical assay) to detect acetaminophen protein adducts...
September 15, 2016: Clinical Gastroenterology and Hepatology
James P Sluka, Xiao Fu, Maciej Swat, Julio M Belmonte, Alin Cosmanescu, Sherry G Clendenon, John F Wambaugh, James A Glazier
We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level...
2016: PloS One
Yuan Gao, Zhijun Cao, Xi Yang, Mohamed A Abdelmegeed, Jinchun Sun, Si Chen, Richard D Beger, Kelly Davis, William F Salminen, Byoung-Joon Song, Donna L Mendrick, Li-Rong Yu
Overdose of acetaminophen (APAP) is a major cause of acute liver failure. To identify pathways related to hepatotoxicity and potential biomarkers of liver injury, a proteomic approach of (16) O/(18) O labeling and 2D-LC-MS/MS was used to analyze liver tissues from rats at 6 and 24 h post-treatment with low (100 mg/kg) and high (1250 mg/kg) doses of APAP. The analysis revealed that molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner...
September 16, 2016: Proteomics. Clinical Applications
Hiromi Kusama, Kazuyoshi Kon, Kenichi Ikejima, Kumiko Arai, Tomonori Aoyama, Akira Uchiyama, Shunhei Yamashina, Sumio Watanabe
BACKGROUND: Acetaminophen (APAP) overdose induces severe oxidative stress followed by hepatocyte apoptosis/necrosis. Previous studies have indicated that endoplasmic reticulum (ER) stress is involved in the cell death process. Therefore, we investigated the effect of the chemical chaperone 4-phenyl butyric acid (PBA) on APAP-induced liver injury in mice. METHODS: Eight-week-old male C57Bl6/J mice were given a single intraperitoneal (i.p.) injection of APAP (450 mg/kg body weight), following which some were repeatedly injected with PBA (120 mg/kg body weight, i...
September 6, 2016: Journal of Gastroenterology
Mustafa Ferudun Çelikmen, Sezgin Sarıkaya, Doğaç Niyazi Özüçelik, Mehmet Şükrü Sever, Kurtuluş Açıksarı, Deniz Maktav Çelikmen, Mustafa Yazıcıoğlu, Ali Kandemir, Halil Doğan, Barış Murat Ayvacı, Derya Özaşır Abuşka, Sıla Sadıllıoğlu
BACKGROUND: The present objective was to evaluate effects of acetaminophen and mannitol on renal function and histopathology in crush injuries. METHODS: Thirty-six rats weighing 370-400 g each were used. No surgery was performed on the first (control) group. The gastrocnemius muscle regions of each rat in the remaining 5 groups were compressed for 2 or 24 hours. In the 4th group, 100 mg/kg acetaminophen was intraperitoneally administered. In the 5th group, 1 g/kg mannitol was administered...
July 2016: Ulusal Travma Ve Acil Cerrahi Dergisi, Turkish Journal of Trauma & Emergency Surgery: TJTES
Yazhen Huo, Sanda Win, Tin Aung Than, Shutao Yin, Min Ye, Hongbo Hu, Neil Kaplowitz
AIM: Antrodia Camphorate (AC) is a mushroom that is widely used in Asian countries to prevent and treat various diseases, including liver diseases. However, the active ingredients that contribute to the biological functions remain elusive. The purpose of the present study is to test the hepatoprotective effect of Antcin H, a major triterpenoid chemical isolated from AC, in murine models of acute liver injury. RESULTS: We found that Antcin H pretreatment protected against liver injury in both acetaminophen (APAP) and galactosamine/tumor necrosis factor (TNF)α models...
October 11, 2016: Antioxidants & Redox Signaling
Ryo Koyama, Ryushin Mizuta
Our previous study suggested that the highly toxic α,β-unsaturated aldehyde acrolein, a byproduct of oxidative stress, plays a major role in acetaminophen-induced liver injury. In this study, to determine the involvement of acrolein in the liver injury and to identify novel therapeutic options for the liver damage, we examined two putative acrolein scavengers, a thiol compound cysteamine and a hydroxylamine N-benzylhydroxylamine, in cell culture and in mice. Our results showed that cysteamine and N-benzylhydroxylamine effectively prevented the cell toxicity of acrolein in vitro and acetaminophen-induced liver injury in vivo, which suggested that acrolein is involved in the liver damage, and these two drugs can be potential therapeutic options for this condition...
September 5, 2016: Journal of Veterinary Medical Science
Shizhen Qin, Yong Zhou, Li Gray, Ulrike Kusebauch, Laurence McEvoy, Daniel J Antoine, Lucy Hampson, Kevin B Park, David Campbell, Juan Caballero, Gustavo Glusman, Xiaowei Yan, Taek-Kyun Kim, Yue Yuan, Kai Wang, Lee Rowen, Robert L Moritz, Gilbert S Omenn, Munir Pirmohamed, Leroy Hood
Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. We demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride...
October 7, 2016: Journal of Proteome Research
Bruna Araujo David, Rafael Machado Rezende, Maísa Mota Antunes, Mônica Morais Santos, Maria Alice Freitas Lopes, Ariane Barros Diniz, Rafaela Vaz Sousa Pereira, Sarah Cozzer Marchesi, Débora Moreira Alvarenga, Brenda Naemi Nakagaki, Alan Moreira Araújo, Daniela Silva Dos Reis, Renata Monti Rocha, Pedro Elias Marques, Woo-Yong Lee, Justin Deniset, Pei Xiong Liew, Stephen Rubino, Laura Cox, Vanessa Pinho, Thiago Mattar Cunha, Gabriel Rocha Fernandes, André Gustavo Oliveira, Mauro Martins Teixeira, Paul Kubes, Gustavo Batista Menezes
BACKGROUND & AIMS: Resident macrophages are derived from yolk sac precursors and seed the liver during embryogenesis. Native cells may be replaced by bone marrow precursors during extensive injuries, irradiation and infections. We investigated the liver populations of myeloid immune cells and their location as well as the dynamics of phagocyte repopulation after full depletion. The effects on liver function due to the substitution of original phagocytes by bone marrow-derived surrogates were also examined...
August 25, 2016: Gastroenterology
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