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Acetaminophen toxicity

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https://www.readbyqxmd.com/read/27913221/role-of-the-inflammasome-in-acetaminophen-induced-liver-injury-and-acute-liver-failure
#1
REVIEW
Benjamin L Woolbright, Hartmut Jaeschke
Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has occurred recently in the literature over whether or not there exists a second phase of injury, mediated by inflammatory processes...
November 29, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/27903287/high-content-imaging-quantification-of-multiple-in-vitro-human-neurogenesis-events-after-neurotoxin-exposure
#2
Xian Wu, Anirban Majumder, Robin Webb, Steven L Stice
BACKGROUND: Our objective was to test neural active compounds in a human developmental neurotoxicity (DNT) model that represents neural tube stages of vulnerability. Previously we showed that 14 days in vitro (DIV 14) was sufficient to generate cryopreserved neuronal cells for post thaw neurite recovery assays. However, short exposure and assessment may not detect toxicants that affect an early neurogenesis continuum, from a mitotic human neural progenitor (hNP) cell population through the course of neurite outgrowth in differentiating neurons...
December 1, 2016: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/27888128/neutrophil-gelatinase-associated-lipocalin-production-negatively-correlates-with-hk-2-cell-impairment-evaluation-of-ngal-as-a-marker-of-toxicity-in-hk-2-cells
#3
Martina Hauschke, Erika Roušarová, Pavel Flídr, Jan Čapek, Antonín Libra, Tomáš Roušar
Neutrophil gelatinase-associated lipocalin is an extracellular protein produced mostly in kidney. Recently, it has become a promising biomarker of renal damage in vivo. On the other hand, the validation of NGAL as a biomarker for nephrotoxicity estimation in vitro has not been characterized in detail yet. Since the HK-2 cells are frequently used human kidney cell line, we aimed to characterize the production of NGAL in these cells and to evaluate NGAL as a possible marker of cell impairment. We used heavy metals (mercury, cadmium), peroxide, drugs (acetaminophen, gentamicin) and cisplatin to mimic nephrotoxicity...
November 22, 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/27886581/a-multi-omic-approach-to-elucidate-low-dose-effects-of-xenobiotics-in-zebrafish-danio-rerio-larvae
#4
Susie S Y Huang, Jonathan P Benskin, Nik Veldhoen, Bharat Chandramouli, Heather Butler, Caren C Helbing, John R Cosgrove
Regulatory-approved toxicity assays such as the OECD Fish Embryo Toxicity Assay (TG236) allow correlation of chemical exposure to adverse morphological phenotypes. However, these assays are ineffective in assessing sub-lethal (i.e. low-dose) effects, or differentiating between similar phenotypes induced by different chemicals. Inclusion of multi-omic analyses in studies investigating xenobiotic action provides improved characterization of biological response, thereby enhancing prediction of toxicological outcomes in whole animals in the absence of morphological effects...
November 18, 2016: Aquatic Toxicology
https://www.readbyqxmd.com/read/27872193/critical-contribution-of-nuclear-factor-erythroid-2-related-factor-2-nrf2-to-electrophile-induced-interleukin-11-production
#5
Takashi Nishina, Yutaka Deguchi, Ryosuke Miura, Soh Yamazaki, Yasuhiro Shinkai, Yuko Kojima, Ko Okumura, Yoshito Kumagai, Hiroyasu Nakano
Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through upregulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces upregulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear...
November 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27846064/serum-acetaminophen-protein-adduct-concentrations-in-pediatric-emergency-department-patients
#6
Kennon Heard, Victoria Anderson, Richard C Dart, Deidre Kile, Eric Lavonas, Jody L Green
: Acetaminophen toxicity is a common cause of pediatric liver failure. The diagnosis may be limited by the short window of detection of acetaminophen in serum. Recently acetaminophen protein adducts (APAP-CYS) have been used as a biomarker with a longer duration of detection. The objective of this study was to describe the serum concentrations of APAP-CYS in pediatric patients with and without reported therapeutic acetaminophen exposure. METHODS: A cross sectional study of children age 1 to <12 years presenting to a pediatric emergency department...
November 14, 2016: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/27842792/drug-toxicities-of-common-analgesic-medications-in-the-emergency-department
#7
REVIEW
Mateusz Ciejka, Khoa Nguyen, Martin H Bluth, Elizabeth Dubey
About 75% of patients present to the emergency department with a complaint of pain. There are multiple prescribed and over-the-counter medications that are available for the treatment of pain. Acetaminophen, opioids, and aspirin are commonly used agents that are available as single agents or in combination with other medications. However, all of these agents are susceptible to toxic overdose, which requires prompt recognition through clinical and laboratory assessment modalities and initiation of therapy to reduce the risk of morbidity and mortality...
December 2016: Clinics in Laboratory Medicine
https://www.readbyqxmd.com/read/27836781/nrf2-mediated-liver-protection-by-esculentoside-a-against-acetaminophen-toxicity-through-the-ampk-akt-gsk3%C3%AE-pathway
#8
Lidong Wang, Songling Zhang, Hang Cheng, Hongming Lv, Genhong Cheng, Xinxin Ci
Acetaminophen (APAP) overdose accounts for the majority of acute liver failure cases, and oxidative stress plays a key role in its toxic effects. Esculentoside A (EsA) has anti-oxidant activities, but its therapeutic potential for APAP hepatotoxicity remains unknown. This study aimed to assess the protective effects and mechanism of EsA against APAP-induced hepatotoxicity in vitro and in vivo. In vitro, EsA treatment inhibited APAP- or H2O2-induced cytotoxicity, H2O2 and O2(-) production, glutathione (GSH) depletion and apoptosis dependent on nuclear factor erythroid-2-related factor 2 (Nrf2) activation in HepG2 cells...
November 9, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27829418/hepatoprotective-potential-of-fagonia-olivieri-dc-against-acetaminophen-induced-toxicity-in-rat
#9
Umbreen Rashid, Muhammad Rashid Khan, Moniba Sajid
BACKGROUND: Fagonia olivieri (DC) being used for the treatment of diabetes, cancer, fever and claimed to be effective in many other stress related disorders. In this study we have evaluated the F. olivieri whole methanol extract and its derived fractions for various in vitro and in vivo antioxidant studies. METHODS: The crude methanol extract of the whole plant of F. olivieri (FOM) and its derived fractions; n-hexane (FOH), chloroform (FOC), ethyl acetate (FOE), n-butanol (FOB) and aqueous (FOA) were evaluated for the total phenolic and flavonoid content and in vitro antioxidant abilities...
November 9, 2016: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/27826632/inhibition-of-pannexin1-channels-alleviates-acetaminophen-induced-hepatotoxicity
#10
Michaël Maes, Mitchell R McGill, Tereza Cristina da Silva, Chloé Abels, Margitta Lebofsky, James L Weemhoff, Taynã Tiburcio, Isabel Veloso Alves Pereira, Joost Willebrords, Sara Crespo Yanguas, Anwar Farhood, Alain Beschin, Jo A Van Ginderachter, Silvia Penuela, Hartmut Jaeschke, Bruno Cogliati, Mathieu Vinken
Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity...
November 8, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/27807796/human-umbilical-cord-blood-derived-neural-stem-cell-line-as-a-screening-model-for-toxicity
#11
Rajashree Patnaik, Rabindra Nath Padhy
The aim was to investigate whether a human neural stem cell (NSC) line derived from human umbilical cord blood (hUCB) can be used for toxicity study. Toxicity of both neurotoxic environmental xenobiotics, methyl mercury chloride (CH3HgCl), lead acetate (CH3COOPb), and chlorpyrifos (CP), and non-neurotoxic insecticide, dichlorvos, as well as non-neurotoxic drugs, theophylline and acetaminophen were assessed. Additionally, differentiation of neuronal and glial cell lines derived from hUCB was elucidated. It was observed that CH3HgCl was more toxic to human NSCs in comparison to CH3COOPb and CP...
November 2, 2016: Neurotoxicity Research
https://www.readbyqxmd.com/read/27794450/3d-engineered-in-vitro-hepatospheroids-for-studying-drug-toxicity-and-metabolism
#12
Swati Chitrangi, Prabha Nair, Aparna Khanna
Drug toxicity is one of the reasons for late stage drug attrition, because of hepatotoxicity. Various in vitro liver models like primary human hepatocytes, immortalized human hepatic cell lines, liver slices and microsomes have been used; but limited by viability, hepatic gene expression and function. The 3D-engineered construct of hepatocyte-like-cells (HLCs) differentiated from stem cells, may provide a limitless source of hepatocytes with improved reproducibility. Towards this end, we used hepatospheroids (diameter=50-80μm) differentiated from human-umbilical-cord-mesenchymal stem cells (hUC-MSCs) on 3D scaffold GEVAC (Gelatin-vinyl-acetate-copolymer) as in vitro model for studying drug metabolism/toxicity...
October 26, 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/27793116/the-incidence-presentation-outcomes-risk-of-mortality-and-economic-data-of-drug-induced-liver-injury-from-a-national-database-in-thailand-a-population-base-study
#13
Abhasnee Sobhonslidsuk, Kittiyod Poovorawan, Ngamphol Soonthornworasiri, Wirichada Pan-Ngum, Kamthorn Phaosawasdi
BACKGROUND: Toxic liver diseases are mainly caused by drug-induced liver injury (DILI). We assessed incidences and outcomes of DILI including associated factors for mortality. METHODS: We performed a population-based study of hospitalized patients with DILI. Information was retrieved from the Nationwide Hospital Admission Data using ICD-10 code of toxic liver diseases (K71) and additional codes (T36-T65). The associated factors were analyzed with log-rank test, univariate and multiple cox regression analysis...
October 28, 2016: BMC Gastroenterology
https://www.readbyqxmd.com/read/27788602/can-a-serum-acetaminophen-concentration-obtained-less-than-4-hours-post-ingestion-determine-which-patients-do-not-require-treatment-with-acetylcysteine
#14
Mark C Yarema, Jason P Green, Marco L A Sivilotti, David W Johnson, Alberto Nettel-Aguirre, Charlemaigne Victorino, Daniel A Spyker, Barry H Rumack
CONTEXT: The interpretation of acetaminophen concentrations obtained prior to 4 hours after an acute, single overdose remains unclear. Patient care decisions in the Emergency Department could be accelerated if such concentrations could reliably exclude the need for treatment. OBJECTIVE: To determine the agreement between a serum acetaminophen concentration obtained less than 4 hours after an acute ingestion and the subsequent 4 + hour concentration, and the predictive accuracy of early concentrations for identifying patients with potentially toxic exposures...
October 28, 2016: Clinical Toxicology
https://www.readbyqxmd.com/read/27773698/differential-susceptibility-to-acetaminophen-induced-liver-injury-in%C3%A2-sub-strains-of-c57bl-6-mice-6n-versus-6j
#15
Luqi Duan, John S Davis, Benjamin L Woolbright, Kuo Du, Mala Cahkraborty, James Weemhoff, Hartmut Jaeschke, Mohammed Bourdi
: Mouse models of acetaminophen (APAP) hepatotoxicity are considered relevant for the human pathophysiology. The C57BL/6 strain is most popular because it is the background strain of gene knock-out mice. However, conflicting results in the literature may have been caused by sub-strain mismatches, e.g. C57BL/6J and C57BL/6N. This study was initiated to determine the mechanism behind the sub-strain susceptibility to APAP toxicity. C57BL/6N and C57BL/6J mice were dosed with 200 mg/kg APAP and sacrificed at different time points...
December 2016: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/27761495/gene-expression-data-from-acetaminophen-induced-toxicity-in-human-hepatic-in-vitro-systems-and-clinical-liver-samples
#16
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
https://www.readbyqxmd.com/read/27717869/withaferin-a-induces-nrf2-dependent-protection-against-liver-injury-role-of-keap1-independent-mechanisms
#17
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
https://www.readbyqxmd.com/read/27689879/mass-spectrometric-and-functional-aspects-of-drug-protein-conjugation
#18
Arun Tailor, James C Waddington, Xiaoli Meng, B Kevin Park
The covalent binding of drugs (metabolites) to proteins to form drug-protein adducts can have an adverse effect on the body. These adducts are thought to be responsible for idiosyncratic drug reactions including severe drug hypersensitivity reactions. Major advances in proteomics technology have allowed for the identification and quantification of target proteins for certain drugs. Human serum albumin (HSA) and Hb have been identified as accessible targets and potential biomarkers for drug-protein adducts formation, for numerous drugs (metabolites) including β-lactam antibiotics, reactive drug metabolites such as quinone imines (acetaminophen) and acyl glucuronides (diclofenac), and covalent inhibitors (neratinib)...
September 30, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27681105/influence-of-volumetric-reduction-factor-during-ozonation-of-nanofiltration-concentrates-for-wastewater-reuse
#19
Antonin Azaïs, Julie Mendret, Eddy Petit, Stephan Brosillon
Global population growth induces increased threat on drinking water resources. One way to address this environmental issue is to reuse water from wastewater treatment plant. The presence of pathogenic microorganisms and potentially toxic organic micropollutants does not allow a direct reuse of urban effluents. Membrane processes such reverse osmosis (RO) or nanofiltration (NF) can be considered to effectively eliminate these pollutants. The integration of membrane processes involves the production of concentrated retentates which require being disposed...
December 2016: Chemosphere
https://www.readbyqxmd.com/read/27680534/comparative-toxicity-and-metabolism-of-n-acyl-homologues-of-acetaminophen-and-its-isomer-3-hydroxyacetanilide
#20
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
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