4,249 results match your criteria Toxicity Acetaminophen


Mechanism-based identification of plasma metabolites associated with liver toxicity.

Toxicology 2020 May 29:152493. Epub 2020 May 29.

Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD 21702, USA. Electronic address:

Early diagnosis of liver injuries caused by drugs or occupational exposures is necessary to enable effective treatments and prevent liver failure. Whereas histopathology remains the gold standard for assessing hepatotoxicity in animals, plasma aminotransferase levels are the primary measures for monitoring liver dysfunction in humans. In this study, using Sprague Dawley rats, we investigated whether integrated analyses of transcriptomic and metabolomic data with genome-scale metabolic models (GSMs) could identify early indicators of injury and provide new insights into the mechanisms of hepatotoxicity. Read More

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http://dx.doi.org/10.1016/j.tox.2020.152493DOI Listing

Human multidrug resistance protein 4 (MRP4) is a cellular efflux transporter for paracetamol glutathione and cysteine conjugates.

Arch Toxicol 2020 May 29. Epub 2020 May 29.

Department of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, The Netherlands.

Paracetamol (acetaminophen, APAP) overdose is a leading cause of acute drug-induced liver failure. APAP hepatotoxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is inactivated by conjugation with glutathione (GSH) to APAP-GSH, which is further converted into its cysteine derivative APAP-CYS. Read More

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http://dx.doi.org/10.1007/s00204-020-02793-4DOI Listing

Mechanism of protection of rat hepatocytes from acetaminophen-induced cellular damage by ethanol extract of .

Interdiscip Toxicol 2019 Dec 30;12(4):169-179. Epub 2020 Apr 30.

School of Biosciences, Mahatma Gandhi University, PD Hills PO, Kottayam, 686560 Kerala, India.

The aim of this study is to evaluate the protective effect of ethanol extract of (EEAL) in preventing acetaminophen induced liver toxicity. EEAL was prepared and its hepatoprotective effect was studied in both isolated primary hepatocytes and in Sprague Dawley rats . For studies, the animals were grouped as Group I - Control; Group II - ACN (2 g/kg b. Read More

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http://dx.doi.org/10.2478/intox-2019-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247370PMC
December 2019

Development of 3D Hepatic Constructs Within Polysaccharide-Based Scaffolds with Tunable Properties.

Int J Mol Sci 2020 May 21;21(10). Epub 2020 May 21.

INSERM U1148, LVTS, Université de Paris, X Bichat Hospital, 46 rue H Huchard, F-75018 Paris, France.

Organoids production is a key tool for in vitro studies of physiopathological conditions, drug-induced toxicity assays, and for a potential use in regenerative medicine. Hence, it prompted studies on hepatic organoids and liver regeneration. Numerous attempts to produce hepatic constructs had often limited success due to a lack of viability or functionality. Read More

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http://dx.doi.org/10.3390/ijms21103644DOI Listing

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury.

Oxid Med Cell Longev 2020 13;2020:8026838. Epub 2020 May 13.

The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. Read More

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http://dx.doi.org/10.1155/2020/8026838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243017PMC

COVID-19 and NSAIDS: A Narrative Review of Knowns and Unknowns.

Pain Ther 2020 May 24. Epub 2020 May 24.

The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Concern about the appropriate role of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 speculate that NSAIDs, in particular ibuprofen, may upregulate the entry point for the virus, the angiotensin-converting enzyme (ACE) 2 receptors and increase susceptibility to the virus or worsen symptoms in existing disease. Adverse outcomes with COVID-19 have been linked to cytokine storm but the most effective way to address exaggerated inflammatory response is complex and unclear. The Expert Working Group on the Commission of Human Medicines in the UK and other organizations have stated that there is insufficient evidence to establish a link between ibuprofen and susceptibility to or exacerbation of COVID-19. Read More

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http://dx.doi.org/10.1007/s40122-020-00173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245573PMC

Genistein protects against acetaminophen-induced liver toxicity through augmentation of SIRT1 with induction of Nrf2 signalling.

Biochem Biophys Res Commun 2020 Jun 27;527(1):90-97. Epub 2020 Apr 27.

The Institute of Infection and Inflammation, Department of Microbiology and Immunology, Medical College, China Three Gorges University, Yichang, 443002, China; Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, School of Pharmacy, Yantai University, Yantai, 264005, China. Electronic address:

Previous studies suggest that genistein protects liver from acetaminophen (APAP)-induced injury, however, the detailed mechanism of the process is still incompletely. Therefore, present study was to investigate the potential mechanism of the genistein mediated protection against APAP-induced hepatotoxicity. As shown, supplementation with 150 mg/kg genistein greatly alleviated the increase in serum alanine aminotransferase (ALT) activity, aspartate aminotransferase (AST) activity, hepatic malondialdehyde (MDA) contents, and reversed the decrease in hepatic GSH levels in response to overdose APAP. Read More

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http://dx.doi.org/10.1016/j.bbrc.2020.04.100DOI Listing

Acetaminophen Tests Battery (ATB): A Comprehensive Method to Study Acetaminophen-Induced Acute Liver Injury.

Gene Expr 2020 May 22. Epub 2020 May 22.

University of Kansas Medical Center.

Acetaminophen (APAP) overdose is the major cause of acute liver failure (ALF) in the Western world. Extensive research is ongoing to identify the mechanisms of APAP-induced ALF. APAP-induced acute liver injury is also one of the most commonly studied drug-induced liver injury models in the field of hepatotoxicity. Read More

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http://dx.doi.org/10.3727/105221620X15901763757677DOI Listing

Systematic Review of Methemoglobinemia in Acetaminophen Poisoning.

QJM 2020 May 19. Epub 2020 May 19.

Hematology and Oncology division, Department of Internal Medicine, Saint Vincent Hospital, Worcester, Massachusetts, United States.

Background: Acetaminophen (N-acetyl-para-aminophenol, paracetamol, (APAP) toxicity is one of the commonly encountered poisonings by emergency physicians. Methemoglobinemia is an uncommon association and rarely seen in APAP poisoning.

Methods: Retrospective analysis of all the published reports on APAP induced methemoglobinemia from 1968 to 2019. Read More

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http://dx.doi.org/10.1093/qjmed/hcaa174DOI Listing

Characterizations of human UDP-glucuronosyltransferase enzymes in the conjugation of p-cresol.

Toxicol Sci 2020 May 18. Epub 2020 May 18.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Katz Group Centre for Pharmacy and Health Research, Room 3-142D, 11361-87 Avenue, T6G 2E1, Edmonton, Alberta, Canada.

p-Cresol is a uremic toxin that is formed by intestinal microbiota and extensively conjugated by first-pass metabolism. p-Cresol glucuronide exerts various forms of cellular toxicity in vitro and is accumulated in the plasma of subjects with kidney disease, where associations with adverse cardiovascular and renal outcomes are evident. The objective of this study was to determine the contributions of human UDP-glucuronosyltransferase (UGT) enzymes in the formation of p-cresol glucuronide. Read More

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http://dx.doi.org/10.1093/toxsci/kfaa072DOI Listing

Hepatoprotective and antioxidant activity of hydroalcoholic extract of on acetaminophen-induced liver toxicity in male rats.

Heliyon 2019 Dec 24;5(12):e03029. Epub 2019 Dec 24.

Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.

Background: Acetaminophen (APAP) at high doses causes adverse side effects such as hepatotoxicity. The aim of the current study was to investigate the hepatoprotective and antioxidant effects of hydroalcoholic extract of (SP) on hepatotoxicity induced by APAP in male rats.

Methods: Adult male Wistar rats were allocated into four groups: control (C), APAP (2 g/kg), APAP + SP (500 mg/kg), and APAP + Silymarin (SM, 100 mg/kg) as positive control group. Read More

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http://dx.doi.org/10.1016/j.heliyon.2019.e03029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201135PMC
December 2019

Omega-3 fatty acids protect against acetaminophen-induced hepatic and renal toxicity in rats through HO-1-Nrf2-BACH1 pathway.

Arch Biochem Biophys 2020 Jul 26;687:108387. Epub 2020 Apr 26.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Although acetaminophen (APAP) is a commonly used analgesic antipyretic drug, hepatotoxicity and nephrotoxicity are common after the overdose. The main mechanism of APAP toxicity is oxidative stress based. Stress may induce the production of heme oxygenase 1 (HO)-1 which is regulated by interleukin (IL)-10 and inhibit the production of tumor necrosis factor-alpha (TNF-α). Read More

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http://dx.doi.org/10.1016/j.abb.2020.108387DOI Listing

Atypical Manifestation of DRESS Syndrome.

Case Rep Gastrointest Med 2020 12;2020:6863582. Epub 2020 Apr 12.

Department of Gastroenterology, Ascension Providence Hospital, Michigan State University College of Human Medicine, Southfield, USA.

The differential for liver transaminases over 1000 units/liter typically includes liver ischemia, acute viral hepatitis, acetaminophen toxicity, and autoimmune hepatitis. Prompt evaluation is imperative as these etiologies can lead to fulminant liver failure. We present a case of transaminases over 1000 units/liter from an atypical etiology. Read More

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http://dx.doi.org/10.1155/2020/6863582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174907PMC

Integration of in vitro data from three dimensionally cultured HepaRG cells and physiologically based pharmacokinetic modeling for assessment of acetaminophen hepatotoxicity.

Regul Toxicol Pharmacol 2020 Apr 18;114:104661. Epub 2020 Apr 18.

Academy of Military Medical Sciences, Beijing, PR China; Center of Disease Control and Prevention, PLA, Beijing, PR China. Electronic address:

Selection of appropriate fit-for-purpose in vitro and in silico models is critical for non-animal safety assessment of chemical-induced hepatoxicity. The present study evaluated the feasibility of integrating in vitro data from three-dimensionally (3D)-cultured HepaRG cells and physiologically based pharmacokinetic (PBPK) modeling to predict chemical-induced liver toxicity. A 3D organoid culture system was established using an ultralow attachment method. Read More

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http://dx.doi.org/10.1016/j.yrtph.2020.104661DOI Listing

Paracetamol affects the expression of detoxification- and reproduction-related genes and alters the life traits of Daphnia magna.

Ecotoxicology 2020 May 16;29(4):398-406. Epub 2020 Apr 16.

Department of Ecology, Jinan University, Guangzhou, 510632, China.

Paracetamol (APAP) is a widely used non-steroidal anti-inflammatory drug and has been frequently detected in aquatic environment. However, limited information is provided about the toxic effects and detoxification mechanism of APAP in aquatic invertebrates. In the present study, the change of life traits of Daphnia magna (e. Read More

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http://dx.doi.org/10.1007/s10646-020-02199-zDOI Listing

[Study on protective effect of water extract from Sabia parviflora on liver injury in mice induced by acetaminophen].

Zhongguo Zhong Yao Za Zhi 2020 Mar;45(6):1433-1439

Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences of China Three Gorges University Yichang 443002, China.

The aim of this study was to observe the protective effect of water extract from Sabia parviflora on mice with acute liver injury induced by acetaminophen, and investigate its possible mechanism. Fifty-eight Kunming mice were divided into 6 groups, 8 in the normal group, 10 in the model group, 10 in the biphenyl diester group, and 10 each in the low, medium and high dose groups. After adaptive feeding for one week, the mice in normal group were intragastrically administered with an equal volume of 0. Read More

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http://dx.doi.org/10.19540/j.cnki.cjcmm.20191112.407DOI Listing

Comparison of toxic responses to acetaminophen challenge in ICR mice originating from different sources.

Lab Anim Res 2019 3;35:16. Epub 2019 Sep 3.

1College of Pharmacy, Pusan National University, Busan, 46241 South Korea.

Acetaminophen (APAP) is the most common antipyretic analgesic worldwide. However, APAP overdose causes severe liver injury, especially centrilobular necrosis, in humans and experimental animals. At therapeutic dosage, APAP is mainly metabolized by sulfation and glucuronidation, and partly by cytochrome P450-mediated oxidation. Read More

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http://dx.doi.org/10.1186/s42826-019-0017-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081583PMC
September 2019

Antioxidative and neurotoxicity effects of acute and chronic exposure of the estuarine polychaete Hediste diversicolor to paracetamol.

Environ Toxicol Pharmacol 2020 Jul 26;77:103377. Epub 2020 Mar 26.

Departmento de Biologia, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal; Centro de Estudos do Ambiente e do Mar (CESAM), University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal. Electronic address:

The presence of anthropogenic drugs in the aquatic ecosystems is a reality nowadays, and a large number of studies have been reporting their putative toxic effects on wildlife. However, the majority of the studies published so far uses standard organisms, whose probability of becoming in contact with drugs in real scenarios of contamination is at least, low. The use of autochthonous organisms in ecotoxicity testing is thus mandatory, and the present study aimed to assess the feasibility of assessing oxidative based stress responses (enzymatic defenses, such as catalase, glutathione-s-transferases, and lipid peroxidation; neurotoxicity as an indirect outcome of oxidizing conditions) on a polychaete species, Hediste diversicolor, after being acutely and chronically exposed to the widely employed drug paracetamol. Read More

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http://dx.doi.org/10.1016/j.etap.2020.103377DOI Listing

Cell-permeable succinate prodrugs rescue mitochondrial respiration in cellular models of acute acetaminophen overdose.

PLoS One 2020 6;15(4):e0231173. Epub 2020 Apr 6.

Department of Clinical Sciences Lund, Mitochondrial Medicine, Lund University, Lund, Sweden.

Acetaminophen is one of the most common over-the-counter pain medications used worldwide and is considered safe at therapeutic dose. However, intentional and unintentional overdose accounts for up to 70% of acute liver failure cases in the western world. Extensive research has demonstrated that the induction of oxidative stress and mitochondrial dysfunction are central to the development of acetaminophen-induced liver injury. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135280PMC

Validation of Reference Genes for Gene Expression Studies by RT-qPCR in HepaRG Cells during Toxicity Testing and Disease Modelling.

Cells 2020 Mar 21;9(3). Epub 2020 Mar 21.

University of Edinburgh Hepatology Laboratory, Chancellor's Building, Edinburgh BioQuarter, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

Gene expression analysis by quantitative real-time polymerase chain reaction (RT-qPCR) is routinely used in biomedical studies. The reproducibility and reliability of the data fundamentally depends on experimental design and data interpretation. Despite the wide application of this assay, there is significant variation in the validation process of gene expression data from research laboratories. Read More

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http://dx.doi.org/10.3390/cells9030770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140694PMC

Fatal acetaminophen poisoning with hepatic microvesicular steatosis in a child after repeated administration of therapeutic doses.

Forensic Sci Int 2020 May 17;310:110258. Epub 2020 Mar 17.

Univ Rennes, Inra, Inserm, Institut NUMECAN - UMR_A 1341, UMR_S 1241, Rennes, France; Department of Forensic Toxicology, Rennes University Hospital, Rennes, France. Electronic address:

Acetaminophen is the leading cause of acute liver failure worldwide following massive ingestion. We present here a fatal acute liver failure after repeated administration of four therapeutic doses of acetaminophen at 4-h intervals in a previously healthy 9-year-old female who presented dental pain after a facial trauma during sport practice. A diagnosis of paracetamol-induced hepatitis was deduced from the clinical picture of fulminant hepatitis and tubular necrosis, the encephalopathy with oedema and without signs of trauma. Read More

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http://dx.doi.org/10.1016/j.forsciint.2020.110258DOI Listing

Long noncoding RNA LINC00844-mediated molecular network regulates expression of drug metabolizing enzymes and nuclear receptors in human liver cells.

Arch Toxicol 2020 May 28;94(5):1637-1653. Epub 2020 Mar 28.

National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, HFT100, Jefferson, AR, 72079, USA.

Noncoding RNAs, such as long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), regulate gene expression in many physiological and pathological processes, including drug metabolism. Drug metabolizing enzymes (DMEs) are critical components in drug-induced liver toxicity. In this study, we used human hepatic HepaRG cells treated with 5 or 10 mM acetaminophen (APAP) as a model system and identified LINC00844 as a toxicity-responsive lncRNA. Read More

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http://dx.doi.org/10.1007/s00204-020-02706-5DOI Listing
May 2020
5.980 Impact Factor

New insights in acetaminophen toxicity: HMGB1 contributes by itself to amplify hepatocyte necrosis in vitro through the TLR4-TRIF-RIPK3 axis.

Sci Rep 2020 Mar 27;10(1):5557. Epub 2020 Mar 27.

Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.

Extracellular release of HMGB1 contributes to acetaminophen-induced liver injury. HMGB1 acts as a danger-associated molecular patterns during this toxic process but the mechanisms of action and targeted cells are incompletely defined. Here we studied, in vitro, the role of HMGB1 in amplifying the acetaminophen-induced hepatocyte necrosis process. Read More

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http://dx.doi.org/10.1038/s41598-020-61270-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101425PMC

Comparison of acetaminophen degradation in UV-LED-based advance oxidation processes: Reaction kinetics, radicals contribution, degradation pathways and acute toxicity assessment.

Sci Total Environ 2020 Jun 17;723:137993. Epub 2020 Mar 17.

Water Resources and Environmental Institute, Xiamen University of Technology, Xiamen 361005, China.

Ultraviolet light emitting diode (UV-LED)-based advanced oxidation processes (AOPs) including UV-LED/chloramine (UV-LED/NHCl), UV-LED/hydrogen peroxide (UV-LED/HO) and UV-LED/persulfate (UV-LED/PS), were adopted for acetaminophen (AAP) removal. Results showed that AAP could be effectively degraded by the hybrid processes compared to solely using with UV irradiation and oxidants. The AAP degradation in the three UV-LED-based AOPs were in the order of UV-LED/PS > UV-LED/HO > UV-LED/NHCl and followed a pseudo-first-order kinetics. Read More

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http://dx.doi.org/10.1016/j.scitotenv.2020.137993DOI Listing

The Bile Acid Receptor GPBAR1 Modulates CCL2/CCR2 Signaling at the Liver Sinusoidal/Macrophage Interface and Reverses Acetaminophen-Induced Liver Toxicity.

J Immunol 2020 May 25;204(9):2535-2551. Epub 2020 Mar 25.

Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Perugia 06132, Italy;

Drug-induced liver injury caused by acetaminophen (acetyl-para-aminophenol [APAP]) is the main cause of acute liver failure and liver transplantation in several Western countries. Whereas direct toxicity exerted by APAP metabolites is a key determinant for early hepatocytes injury, the recruitment of cells of innate immunity exerts a mechanistic role in disease progression, determining the clinical outcomes. GPBAR1 is a G protein-coupled receptor for secondary bile acids placed at the interface between liver sinusoidal cells and innate immunity. Read More

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http://dx.doi.org/10.4049/jimmunol.1901427DOI Listing

Gut-Resident Lactobacilli Activate Hepatic Nrf2 and Protect Against Oxidative Liver Injury.

Cell Metab 2020 May 25;31(5):956-968.e5. Epub 2020 Mar 25.

Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

Many studies have suggested a role for gut-resident microbes (the "gut microbiome") in modulating host health; however, the mechanisms by which they impact systemic physiology remain largely unknown. In this study, metabolomic and transcriptional profiling of germ-free and conventionalized mouse liver revealed an upregulation of the Nrf2 antioxidant and xenobiotic response in microbiome-replete animals. Using a Drosophila-based screening assay, we identified members of the genus Lactobacillus capable of stimulating Nrf2. Read More

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http://dx.doi.org/10.1016/j.cmet.2020.03.006DOI Listing

Ibrutinib-associated Arthralgias/Myalgias in Patients With Chronic Lymphocytic Leukemia: Incidence and Impact on Clinical Outcomes.

Clin Lymphoma Myeloma Leuk 2020 Feb 27. Epub 2020 Feb 27.

Division of Hematology/Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA.

Introduction: The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has transformed the treatment of chronic lymphocytic leukemia (CLL), leading to unprecedented improvements in progression-free and overall survival for all patients, including those with poor prognostic features. The side effect profile of ibrutinib is unique compared with chemoimmunotherapy and includes atrial fibrillation, increased bleeding risk, and arthralgias/myalgias. Although common, arthralgias/myalgias and their management are poorly described. Read More

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http://dx.doi.org/10.1016/j.clml.2020.02.001DOI Listing
February 2020

Testing of acetaminophen in support of the international multilaboratory in vivo rat Pig-a assay validation trial.

Environ Mol Mutagen 2020 Mar 18. Epub 2020 Mar 18.

Janssen Research & Development, Beerse, Antwerp, Belgium.

Acetaminophen, a nonmutagenic compound as previously concluded from bacteria, in vitro mammalian cell, and in vivo transgenic rat assays, presented a good profile as a nonmutagenic reference compound for use in the international multilaboratory Pig-a assay validation. Acetaminophen was administered at 250, 500, 1,000, and 2,000 mg·kg ·day to male Sprague Dawley rats once daily in 3 studies (3 days, 2 weeks, and 1 month with a 1-month recovery group). The 3-Day and 1-Month Studies included assessments of the micronucleus endpoint in peripheral blood erythrocytes and the comet endpoint in liver cells and peripheral blood cells in addition to the Pig-a assay; appropriate positive controls were included for each assay. Read More

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http://dx.doi.org/10.1002/em.22368DOI Listing

Role of silymarin () in the prevention of colistin-induced acute nephrotoxicity in rats.

Drug Chem Toxicol 2020 Mar 16:1-8. Epub 2020 Mar 16.

Department of Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey.

Silymarin (Silybum marianum) has some protective effects against drug toxicity (cisplatin, acetaminophen, adriamycin, gentamicin etc.). Colistin is a strong antimicrobial, which is frequently used in the treatment of resistant gram-negative bacterial infections in recent years although it has nephrotoxic potential. Read More

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http://dx.doi.org/10.1080/01480545.2020.1733003DOI Listing

Peroxiredoxin 6 mediates acetaminophen-induced hepatocyte death through JNK activation.

Redox Biol 2020 May 8;32:101496. Epub 2020 Mar 8.

College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong 1-ro 194-31, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea. Electronic address:

Acetaminophen (APAP) is one of the most frequently used drugs; however, its overdose leads to acute liver injury. Recently, studies have reported that the adduction of peroxiredoxin 6 (PRDX6), a member of the PRDX family of antioxidant enzymes, is associated with liver diseases. However, the role of PRDX6 in APAP-induced liver injury remains unclear. Read More

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http://dx.doi.org/10.1016/j.redox.2020.101496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068129PMC

Mechanisms and pathophysiological significance of sterile inflammation during acetaminophen hepatotoxicity.

Food Chem Toxicol 2020 Apr 4;138:111240. Epub 2020 Mar 4.

Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA. Electronic address:

Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. Read More

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http://dx.doi.org/10.1016/j.fct.2020.111240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098420PMC

Three-Dimensional Spheroids With Primary Human Liver Cells and Differential Roles of Kupffer Cells in Drug-Induced Liver Injury.

J Pharm Sci 2020 Jun 5;109(6):1912-1923. Epub 2020 Mar 5.

Corning Life Sciences, Bedford, Massachusetts 01730.

Drug-induced liver injury (DILI) remains a challenge and a leading risk for drug discovery. Three-dimensional liver spheroids made from primary human hepatocytes (PHHs) with, or without, other liver cell types can provide more physiological relevance. In comparison to conventional 2-dimensional monolayer culture, our tests with 100 drugs of known DILI status indicate that PHH spheroids are significantly more sensitive in detecting drug-induced hepatotoxicity. Read More

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http://dx.doi.org/10.1016/j.xphs.2020.02.021DOI Listing
June 2020
2.590 Impact Factor

Public awareness of acetaminophen and risks of drug induced liver injury: Results of a large outpatient clinic survey.

PLoS One 2020 4;15(3):e0229070. Epub 2020 Mar 4.

Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada.

Acetaminophen is one of the most commonly consumed analgesics world wide. Generally perceived as a safe medication, it is the most common cause of acute liver failure in the United States with inadvertent hepatotoxicity in half of all cases. We therefore conducted a survey on the public perceptions of acetaminophen in patients attending the outpatient clinic in Vancouver, Canada. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055817PMC

Probiotic Bacillus Spores Protect Against Acetaminophen Induced Acute Liver Injury in Rats.

Nutrients 2020 Feb 27;12(3). Epub 2020 Feb 27.

Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania.

Acetaminophen (APAP) is one of the most used analgesics and antipyretic agents in the world. Intoxication with APAP is the main cause of acute liver toxicity in both the US and Europe. Spore-forming probiotic bacteria have the ability to resist harsh gastric and intestinal conditions. Read More

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http://dx.doi.org/10.3390/nu12030632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146158PMC
February 2020

Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity.

Arch Toxicol 2020 Apr 28;94(4):1251-1263. Epub 2020 Feb 28.

CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.

In addition to hepatocytes, the liver comprises a host of specialised non-parenchymal cells which are important to consider in the development of in vitro models which are both physiologically and toxicologically relevant. We have characterized a 3D co-culture system comprising primary human hepatocytes (PHH) and non-parenchymal cells (NPC) and applied it to the investigation of acetaminophen-induced toxicity. Firstly, we titrated ratios of PHH:NPC and confirmed the presence of functional NPCs via both immunohistochemistry and activation with both LPS and TGF-β. Read More

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http://dx.doi.org/10.1007/s00204-020-02682-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225187PMC

Comparative Study of Protective Effect of Cimetidine and Verapamil on Paracetamol-Induced Hepatotoxicity in Mice.

Int J Hepatol 2020 23;2020:9185361. Epub 2020 Jan 23.

Department of Pharmacology, National Institute of Health (NIH), Islamabad, Pakistan.

Paracetamol, chemically known as acetaminophen, if taken in higher doses has hepatotoxic potential. Cimetidine by inhibiting the cytochromal enzymes and reducing the production of the toxic metabolite can reduce the hepatotoxic potential while Verapamil can act as a hepatoprotective by maintaining calcium homeostasis. The present study was conducted to study the hepatoprotective activity of Cimetidine and Verapamil against the toxicity induced by paracetamol. Read More

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http://dx.doi.org/10.1155/2020/9185361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998752PMC
January 2020

The MicroRNA-based Liquid Biopsy Improves Early Assessment of Lethal Acetaminophen Poisoning: A Case Report.

Am J Case Rep 2020 Feb 22;21:e919289. Epub 2020 Feb 22.

Drug Safety Research and Development, Pfizer, Inc., Groton, CT, USA.

BACKGROUND Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction of the outcome of the acetaminophen overdose are needed. Recently, using next-generation sequencing analysis of serum from human study participants we uncovered injury-specific signatures of circulating microRNAs (miRNAs) that represented underlying molecular mechanisms of toxicity. Read More

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http://dx.doi.org/10.12659/AJCR.919289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049075PMC
February 2020

Upregulation of Nrf2- related cytoprotective genes expression by acetaminophen-induced acute hepatotoxicity in mice and the protective role of betaine.

Hum Exp Toxicol 2020 Feb 21:960327120905962. Epub 2020 Feb 21.

Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Overdose of acetaminophen (APAP) is the main reason for acute liver failure. Oxidative stress is associated with hepatotoxicity caused by APAP. Betaine is a methyl donor and -adenosylmethionine precursor. Read More

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http://dx.doi.org/10.1177/0960327120905962DOI Listing
February 2020

The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity.

Int Immunopharmacol 2020 Apr 14;81:106292. Epub 2020 Feb 14.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Acetaminophen (APAP)-induced hepatotoxicity comes among the most frequent humans' toxicities caused by drugs. So far, therapeutic interventions for such type of drug-induced toxicity are still limited. In the current study, we examined the influence of capmatinib (Cap), a novel c-Met inhibitor, on APAP-induced hepatotoxicity in mice when administered 2 h prior, 2 h post and 4 h post APAP-challenge. Read More

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http://dx.doi.org/10.1016/j.intimp.2020.106292DOI Listing

Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure.

Toxicol Sci 2020 May;175(1):87-97

Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington, London SW7 2AZ, UK.

The metabolic fate, toxicity, and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/l using maintenance doses of 0.5-4 g/h until ALF. Read More

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http://dx.doi.org/10.1093/toxsci/kfaa023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197950PMC

Elevated procalcitonin levels in patients with acetaminophen intoxication: two case reports: A CARE-compliant article.

Medicine (Baltimore) 2020 Feb;99(7):e18882

Department of Emergency Medicine, Kangdong Sacred Heart Hospital, Hallym University School of Medicine, Seoul, Republic of Korea.

Rationale: Procalcitonin (PCT) is used as a biomarker for identifying the occurrence of sepsis. Previous studies have reported high levels of PCT with acetaminophen intoxication without evidence of infection. Here, we report two patients with acetaminophen intoxication with high levels of PCT without showing any symptoms of bacterial infection. Read More

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http://dx.doi.org/10.1097/MD.0000000000018882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035086PMC
February 2020

Knockdown of Long Noncoding RNAs Hepatocyte Nuclear Factor 1 Antisense RNA 1 and Hepatocyte Nuclear Factor 4 Antisense RNA 1 Alters Susceptibility of Acetaminophen-Induced Cytotoxicity in HepaRG Cells.

Mol Pharmacol 2020 04 6;97(4):278-286. Epub 2020 Feb 6.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (L.C., P.W., J.E.M., X.-b.Z.) and Department of Pharmacology, School of Basic Medicine, Zhengzhou University, Zhengzhou, Henan, China (P.W.)

Acetaminophen (APAP) is a commonly used over-the-counter drug for its analgesic and antipyretic effects. However, APAP overdose leads to severe APAP-induced liver injury (AILI) and even death as a result of the accumulation of -acetyl--benzoquinone imine, the toxic metabolite of APAP generated by cytochrome P450s (P450s). Long noncoding RNAs HNF1 antisense RNA 1 (HNF1-AS1) and HNF4 antisense RNA 1 (HNF4-AS1) are regulatory RNAs involved in the regulation of P450 expression in both mRNA and protein levels. Read More

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http://dx.doi.org/10.1124/mol.119.118778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045890PMC

Suppression of glomerular damage and apoptosis and biomarkers of acute kidney injury induced by acetaminophen toxicity using a combination of resveratrol and quercetin.

Drug Chem Toxicol 2020 Feb 3:1-7. Epub 2020 Feb 3.

Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia.

Acute renal failure induced by a toxic dose of acetaminophen (also known as paracetamol, or APAP) is common in both humans and experimental animal models. Glomerular ultrastructural alterations induced by APAP overdose associated with the suppression of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic antioxidants and anti-inflammatory compounds, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced nephrotoxicity. Read More

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http://dx.doi.org/10.1080/01480545.2020.1722156DOI Listing
February 2020

Acetaminophen-induced hepatotoxicity of cultured hepatocytes depends on timing of isolation from light-cycle controlled mice.

Genes Cells 2020 Apr 27;25(4):257-269. Epub 2020 Feb 27.

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama-shi, Japan.

Most physiological changes follow a daily cycle in animals because their circadian rhythm is adjusted to and synchronized with sunlight. In particular, the circadian rhythm affects liver functions, including pharmacokinetics and metabolism. The influence of circadian rhythm has not been included in hepatotoxicity assays used in drug discovery and development. Read More

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http://dx.doi.org/10.1111/gtc.12755DOI Listing

Histopathological changes of acetaminophen-induced liver injury and subsequent liver regeneration in BALB/C and ICR mice.

Vet World 2019 Nov 4;12(11):1682-1688. Epub 2019 Nov 4.

Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.

Background And Aim: Laboratory mice are widely used as a research model to provide insights into toxicological studies of various xenobiotic. Acetaminophen (APAP) is an antipyretic and analgesic drug that is commonly known as paracetamol, an ideal hepatotoxicant to exhibit centrilobular necrosis in laboratory mice to resemble humans. However, assessment of histopathological changes between mouse strains is important to decide the optimal mouse model used in APAP toxicity study. Read More

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http://dx.doi.org/10.14202/vetworld.2019.1682-1688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925052PMC
November 2019

Toxicological Property of Acetaminophen: The Dark Side of a Safe Antipyretic/Analgesic Drug?

Biol Pharm Bull 2020 ;43(2):195-206

Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Sojo University.

Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. Read More

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http://dx.doi.org/10.1248/bpb.b19-00722DOI Listing
January 2020

Evaluating lactate prognostic value in children suspected of acetaminophen-induced liver failure in Liberia.

Pediatr Res 2020 Jan 29. Epub 2020 Jan 29.

Médecins Sans Frontières - Operational Centre Paris, Paris, France.

Background: The prognostic significance of hyperlactatemia in young children with liver injury suspected to be attributed to repeated supratherapeutic doses of acetaminophen remain understudied.

Methods: We conducted a retrospective medical chart review including children aged <5 years admitted with hepatocellular injury. The study was conducted in Bardnesville Junction Hospital operated by Médecins Sans Frontières in Monrovia, Liberia. Read More

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http://dx.doi.org/10.1038/s41390-020-0783-zDOI Listing
January 2020

Acute Liver Failure (ALF) in Pregnancy: How Much Is Pregnancy-Related?

Hepatology 2020 Jan 28. Epub 2020 Jan 28.

Division of Digestive and Liver Diseases, UT Southwestern Medical Center at Dallas, Dallas, TX.

Background: Acute liver failure (ALF), characterized by sudden onset of coagulopathy (INR ≥ 1.5) and encephalopathy may occur during pregnancy, either as a pregnancy-associated etiology or as an unrelated and co-incidental liver injury. The U. Read More

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http://dx.doi.org/10.1002/hep.31144DOI Listing
January 2020

The molecular mechanism underlining the preventive effect of vitamin D against hepatic and renal acute toxicity through the NrF2/ BACH1/ HO-1 pathway.

Life Sci 2020 Mar 20;244:117331. Epub 2020 Jan 20.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Aim: Drug-induced liver and kidney injuries are worldwide problems that cause restrictions in the use of drugs. The injury is highly mediated by oxidative stress and inflammation pathways. So, demonstrating the role of the natural compound (Vit. Read More

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http://dx.doi.org/10.1016/j.lfs.2020.117331DOI Listing

Acetaminophen affects the survivor, pigmentation and development of craniofacial structures in zebrafish (Danio rerio) embryos.

Biochem Pharmacol 2020 Apr 20;174:113816. Epub 2020 Jan 20.

Departamento de Zoología Genética y Antropología Física, Facultad de Veterinaria, Universidade de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain. Electronic address:

In spite of its toxic effects, N-acetyl-p-aminophenol (APAP), also commonly known as acetaminophen or paracetamol, is one of the most widely used analgesic and antipyretic agents. It can be obtained without a medical prescription. To test the effect over the zebrafish embryonic development, a Fish Embryo acute Toxicity (FET) test was carried out with acetaminophen to establish the range of concentrations that cause a harmful effect on the zebrafish development. Read More

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http://dx.doi.org/10.1016/j.bcp.2020.113816DOI Listing