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Acetaminophen toxicity

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https://www.readbyqxmd.com/read/28104395/methionine-sulfoxide-reductase-a-deficiency-exacerbates-acute-liver-injury-induced-by-acetaminophen
#1
Mahendra Pratap Singh, Ki Young Kim, Hwa-Young Kim
Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA(-/-)). We found that MsrA(-/-) mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA(+/+))...
January 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28099803/deep-learning-to-predict-the-formation-of-quinone-species-in-drug-metabolism
#2
Tyler B Hughes, S Joshua Swamidass
Many adverse drug reactions are thought to be caused by electrophilically reactive drug metabolites that conjugate to nucleophilic sites within DNA and proteins, causing cancer or toxic immune responses. Quinone species, including quinone-imines, quinone-methides, and imine-methides, are electrophilic Michael acceptors that are of- ten highly reactive, and comprise over 40% of all known reactive metabolites. Quinone metabolites are created by cytochromes P450 and peroxidases. For example, cy- tochromes P450 oxidize acetaminophen to N-acetyl-p-benzoquinone imine, which is electrophilically reactive and covalently binds to nucleophilic sites within proteins...
January 18, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28088388/activation-of-gr-but-not-pxr-by-dexamethasone-attenuated-acetaminophen-hepatotoxicities-via-fgf21-induction
#3
Saurabh G Vispute, Pengli Bu, Yuan Le, Xingguo Cheng
Glucocorticoid receptor (GR) signaling is indispensable for cell growth and development, and plays important roles in drug metabolism. Fibroblast growth factor (Fgf) 21, an important regulator of glucose, lipid, and energy metabolism, plays a cytoprotective role by attenuating toxicities induced by chemicals such as dioxins, acetaminophen (APAP), and alcohols. The present study investigates the impact of dexamethasone (DEX)-activated GR on Fgf21 expression and how it affects the progression of APAP-induced hepatotoxicity...
January 11, 2017: Toxicology
https://www.readbyqxmd.com/read/28070111/a-monkey-model-of-acetaminophen-induced-hepatotoxicity-phenotypic-similarity-to-human
#4
Satoshi Tamai, Takuma Iguchi, Noriyo Niino, Kei Mikamoto, Ken Sakurai, Ayako Sayama, Hitomi Shimoda, Wataru Takasaki, Kazuhiko Mori
Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28064122/correlation-between-degradation-pathway-and-toxicity-of-acetaminophen-and-its-by-products-by-using-the-electro-fenton-process-in-aqueous-media
#5
Thi Xuan Huong Le, Thi Van Nguyen, Zoulkifli Amadou Yacouba, Laetitia Zoungrana, Florent Avril, Duy Linh Nguyen, Eddy Petit, Julie Mendret, Valerie Bonniol, Mikhael Bechelany, Stella Lacour, Geoffroy Lesage, Marc Cretin
The evolution of the degradation by-products of an acetaminophen (ACE) solution was monitored by HPLC-UV/MS and IC in parallel with its ecotoxicity (Vibrio fischeri 81.9%, Microtox(®) screening tests) during electro-Fenton (EF) oxidation performed on carbon felt. The aromatic compounds 2-hydroxy-4-(N-acetyl) aminophenol, 1,4-benzoquinone, benzaldehyde and benzoic acid were identified as toxic sub-products during the first stage of the electrochemical treatment, whereas aliphatic short-chain carboxylic acids (oxalic, maleic, oxamic, formic, acetic and fumaric acids) and inorganic ions (ammonium and nitrate) were well identified as non-toxic terminal sub-products...
December 21, 2016: Chemosphere
https://www.readbyqxmd.com/read/28031524/adenosine-5-monophosphate-blocks-acetaminophen-toxicity-by-increasing-ubiquitination-mediated-ask1-degradation
#6
Xiao Yang, Yibei Zhan, Qi Sun, Xi Xu, Yi Kong, Jianfa Zhang
Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure in the world. Hepatic c-jun NH2-terminal protein kinase (JNK) activation is thought to be a consequence of oxidative stress produced during APAP metabolism. Activation of JNK signals causes hepatocellular damage with necrotic and apoptotic cell death. Here we found that APAP caused a feedback increase in plasma adenosine 5'-monophsphate (5'-AMP). We demonstrated that co-administration of APAP and 5'-AMP significantly ameliorated APAP-induced hepatotoxicity in mice, without influences on APAP metabolism and its analgesic function...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27989119/biomonitoring-human-albumin-adducts-the-past-the-present-and-the-future
#7
Gabriele Sabbioni, Robert J Turesky
Serum albumin (Alb) is the most abundant protein in blood plasma. Alb reacts with many carcinogens and/or their electrophilic metabolites. Studies conducted over 20 years ago showed that Alb forms adducts with the human carcinogens aflatoxin B1 and benzene, which were successfully used as biomarkers in molecular epidemiology studies designed to address the role of these chemicals in cancer risk. Alb forms adducts with many therapeutic drugs or their reactive metabolites such as β-lactam antibiotics, acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, and antiretroviral therapy drugs...
January 17, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27984590/competing-mechanistic-hypotheses-of-acetaminophen-induced-hepatotoxicity-challenged-by-virtual-experiments
#8
Andrew K Smith, Brenden K Petersen, Glen E P Ropella, Ryan C Kennedy, Neil Kaplowitz, Murad Ookhtens, C Anthony Hunt
Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon...
December 2016: PLoS Computational Biology
https://www.readbyqxmd.com/read/27960556/acetaminophen-toxicity-in-rat-and-mouse-hepatocytes-in-vitro
#9
Otto Kučera, René Endlicher, David Rychtrmoc, Halka Lotková, Ondřej Sobotka, Zuzana Červinková
CONTEXT: Acetaminophen (APAP) hepatotoxicity is often studied in primary cultures of hepatocytes of various species, but there are only few works comparing interspecies differences in susceptibility of hepatocytes to APAP in vitro. OBJECTIVES: The aim of our work was to compare hepatotoxicity of APAP in rat and mouse hepatocytes in primary cultures. MATERIALS AND METHODS: Hepatocytes isolated from male Wistar rats and C57Bl/6J mice were exposed to APAP for up to 24 h...
December 14, 2016: Drug and Chemical Toxicology
https://www.readbyqxmd.com/read/27913221/role-of-the-inflammasome-in-acetaminophen-induced-liver-injury-and-acute-liver-failure
#10
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
#11
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
#12
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...
March 2017: 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
#13
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...
January 2017: 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
#14
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 up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation 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...
January 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27846064/serum-acetaminophen-protein-adduct-concentrations-in-pediatric-emergency-department-patients
#15
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
#16
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
#17
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...
December 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27829418/hepatoprotective-potential-of-fagonia-olivieri-dc-against-acetaminophen-induced-toxicity-in-rat
#18
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
#19
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
#20
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
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