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Drug induced liver injury

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https://www.readbyqxmd.com/read/28636309/quantitative-chemical-proteomic-profiling-of-the-in-vivo-targets-of-reactive-drug-metabolites
#1
Landon R Whitby, R Scott Obach, Gabriel M Simon, Matthew M Hayward, Benjamin F Cravatt
Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e...
June 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28634823/a-nationwide-study-of-the-incidence-rate-of-herb-induced-liver-injury-in-korea
#2
Jung-Hyo Cho, Dal-Seok Oh, Sang-Hoon Hong, Heung Ko, Nam-Hun Lee, Sang-Eun Park, Chang-Woo Han, Seung-Mo Kim, Young-Chul Kim, Kang-San Kim, Chang-Won Choi, Seon-My Shin, Ki-Tae Kim, Hong-Sik Choi, Jang-Hoon Lee, Jun-Young Kim, Ji-Young Kang, Dong-Soo Lee, Yo-Chan Ahn, Chang-Gue Son
Discrepant incidence has been reported regarding the incidence of herb-induced liver injury (HILI). To address the growing worldwide concern of HILI, we evaluated the risk of HILI in a nationwide prospective study. Between April 2013 and January 2016, 1001 inpatients (360 males and 641 females) from 10 tertiary hospitals throughout South Korea were treated with herbal drugs and had their liver enzymes periodically measured. A total of six patients met the criteria for HILI with RUCAM scores ranging from 4 to 7...
June 20, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28634393/a-small-molecule-ds44170716-inhibits-ca-2-induced-mitochondrial-permeability-transition
#3
Naohiro Kon, Atsushi Satoh, Naoki Miyoshi
Mitochondria are involved in a variety of physiological and pathological processes. Ca(2+) uptake is one of the important functions of the organelle for maintenance of cellular Ca(2+) homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca(2+) overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634377/hepatoprotective-and-in-vitro-antioxidant-effects-of-native-depolymerised-exopolysaccharides-derived-from-termitomyces-albuminosus
#4
Huajie Zhao, Juan Li, Jianjun Zhang, Xiuxiu Wang, Min Liu, Chen Zhang, Le Jia
In this study, native depolymerised-exopolysaccharides (DEPS) were successfully derived from the exopolysaccharides (EPS) of Termitomyces albuminosus, and its hepatoprotective effects against a high-fat emulsion and in vitro antioxidant activities were investigated. Based on the results of in vitro assays, DEPS showed superior antioxidant activities compared with EPS dose-dependently. According to the in vivo assays both EPS and DEPS significantly decreased the lipid levels, improved the enzymatic activities, and reduced lipid peroxidation in both serum and hepatic homogenates...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28633424/three-dimensional-3d-heparg-spheroid-model-with-physiologically-relevant-xenobiotic-metabolism-competence-and-hepatocyte-functionality-for-liver-toxicity-screening
#5
Sreenivasa C Ramaiahgari, Suramya Waidyanatha, Darlene Dixon, Michael J DeVito, Richard S Paules, Stephen S Ferguson
Effective prediction of human responses to chemical and drug exposure is of critical importance in environmental toxicology research and drug development. While significant progress has been made to address this challenge using in vitro liver models, these approaches often fail due to inadequate tissue model functionality. Herein, we describe the development, optimization, and characterization of a novel three-dimensional (3D) spheroid model using differentiated HepaRG cells that achieve and maintain physiologically-relevant levels of xenobiotic metabolism (CYP1A2, CYP2B6, and CYP3A4/5)...
June 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28627888/investigation-of-drug-induced-hepatotoxicity-and-its-remediation-pathway-with-reaction-based-fluorescent-probes
#6
Dan Cheng, Wang Xu, Lin Yuan, Xiao-Bing Zhang
Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO-) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction based fluorescent probes (Naph-ONOO- and Rhod-ONOO-) for ONOO- through a novel and universally applicable mechanism: ONOO- mediated deprotection of -keto caged fluorophores. Among them, Rhod-ONOO- can selectively accumulate and react in mitochondria, one of the main sources of ONOO-, with a substantial lower nano-molar sensitivity of 43 nM...
June 19, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28626835/disrupted-er-to-golgi-trafficking-underlies-anti-hiv-drugs-and-alcohol-induced-cellular-stress-and-hepatic-injury
#7
Hui Han, Yuxin He, Jay Hu, Rhema Lau, Harrison Lee, Cheng Ji
Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in anti-human immunodeficiency virus (HIV) drugs and alcohol-induced liver disease in a significant number of patients infected with HIV. However, the precise mechanism by which the drugs and alcohol cause ER stress remains elusive. We found that ritonavir-boosted lopinavir (RL) activated two canonical UPR branches without activation of the third canonical activating transcription factor 6 (ATF6) branch in either HepG2 cells or primary mouse hepatocytes...
April 2017: Hepatol Commun
https://www.readbyqxmd.com/read/28619387/evaluation-of-ameliorative-ability-of-silibinin-against-zidovudine-and-isoniazid-induced-hepatotoxicity-and-hyperlipidaemia-in-rats-role-of-silibinin-in-phase-i-and-ii-drug-metabolism
#8
Raghu Ramanathan, Karthikeyan Sivanesan
HIV/AIDS patients have suppressed immune system, making them vulnerable to many opportunistic infections including tuberculosis (TB). The patients who are co-infected with TB undergo combined regimens with anti-retroviral drugs such as zidovudine (AZT) and anti-tubercular drug such as isoniazid (INH) for therapy leading to hepatotoxicty. Silibinin (SBN), extracted from Silybum marianum commonly called as "Milk thistle" is used against several drugs-induced hepatotoxicity. The present study evaluates the ameliorative effect of SBN against AZT alone, INH alone, and INH + AZT-induced toxic insults to liver of rats...
June 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28617228/prediction-models-for-drug-induced-hepatotoxicity-by-using-weighted-molecular-fingerprints
#9
Eunyoung Kim, Hojung Nam
BACKGROUND: Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. RESULTS: In this study, we used 881 bits of molecular fingerprint and used as features describing presence or absence of each substructure of compounds...
May 31, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28616908/-the-correlation-between-micrornas-in-serum-and-the-extent-of-liver-injury
#10
Yi-Nan Zuo, Xue-Ling He, Xue-Ni Shi, Shi-Hang Wei, Hai-Lin Yin
OBJECTIVES: To investigate the correlation between the absolute quantification of the microRNAs (miR-122, miR-451, miR-92a, miR-192) in serum during acute liver injury and the extent of liver injury on rat models of CCl4 induced acute liver injury and mice models of acetaminophen (APAP) induced acute liver injury. Furthermore, to investigate the correlation between the absolute quantification of microRNAs in serum and the drug induced liver injury pathological scoring system (DILI-PSS)...
May 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28615926/mechanistic-modelling-of-drug-induced-liver-injury-investigating-the-role-of-innate-immune-responses
#11
Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration...
2017: Gene Regulation and Systems Biology
https://www.readbyqxmd.com/read/28615012/moxifloxacin-monotherapy-versus-combination-therapy-in-patients-with-severe-community-acquired-pneumonia-evoked-ards
#12
Tim Rahmel, Sven Asmussen, Jan Karlik, Jörg Steinmann, Michael Adamzik, Jürgen Peters
BACKGROUND: We tested the hypothesis that moxifloxacin monotherapy is equally effective and safe as a betalactam antibiotic based combination therapy in patients with acute respiratory distress syndrome (ARDS) evoked by severe community acquired pneumonia (CAP). METHODS: In a retrospective chart review study of 229 patients with adult respiratory distress syndrome (ARDS) admitted to our intensive care unit between 2001 and 2011, 169 well-characterized patients were identified to suffer from severe CAP...
June 14, 2017: BMC Anesthesiology
https://www.readbyqxmd.com/read/28612667/all-that-glitters-yellow-is-not-gold-presentation-and-pathophysiology-of-bile-cast-nephropathy
#13
Mitchell Pitlick, Prerna Rastogi
BACKGROUND: Acute kidney injury (AKI) often manifests in patients with liver disease because of a prerenal cause and presents as acute tubular necrosis or hepatorenal syndrome. Distinguishing between these entities is important for prognosis and treatment. Some patients may develop AKI related to their underlying liver disease: for example, membranoproliferative glomerulonephritis or IgA nephropathy. Bile cast nephropathy is an often ignored differential diagnosis of AKI in the setting of obstructive jaundice...
June 1, 2017: International Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28612260/utility-of-spherical-human-liver-microtissues-for-prediction-of-clinical-drug-induced-liver-injury
#14
William R Proctor, Alison J Foster, Jennifer Vogt, Claire Summers, Brian Middleton, Mark A Pilling, Daniel Shienson, Monika Kijanska, Simon Ströbel, Jens M Kelm, Paul Morgan, Simon Messner, Dominic Williams
Drug-induced liver injury (DILI) continues to be a major source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. Accordingly, there is a need for more predictive tools to assess hepatotoxicity risk in drug discovery. Three-dimensional (3D) spheroid hepatic cultures have emerged as promising tools to assess mechanisms of hepatotoxicity, as they demonstrate enhanced liver phenotype, metabolic activity, and stability in culture not attainable with conventional two-dimensional hepatic models...
June 13, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28612092/involvement-of-cytochrome-p450-in-cisplatin-treatment-implications-for-toxicity
#15
REVIEW
Júlia Coelho França Quintanilha, Vanessa Marcilio de Sousa, Marília Berlofa Visacri, Laís Sampaio Amaral, Roseane Maria Maia Santos, Tomás Zambrano, Luis Antonio Salazar, Patricia Moriel
PURPOSE: The aim of this study is to evaluate the relationship between the CYP450 enzyme family and cisplatin toxicity. METHODS: This article examined a collection of studies suggesting that CYP450 enzymes may influence cisplatin toxicity. We performed a narrative mini-review. RESULTS: The studies review showed that CYP450 enzymes have an important role in drug-induced hepatotoxicity and nephrotoxicity, mainly CYP2E1 and CYP4A11. The studies also suggested that the cisplatin and CYP2E1 interaction leads to the generation of reactive oxygen species (ROS) and other oxidants resulting in renal injury; and that ROS generated by both the use of cisplatin and by the CYP2E1 increases tissue damage, induces apoptosis, and causes liver failure...
June 13, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28606651/mechanisms-of-bile-acid-mediated-inflammation-in-the-liver
#16
REVIEW
Man Li, Shi-Ying Cai, James L Boyer
Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models...
June 9, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28606603/identification-of-enzymes-responsible-for-nitrazepam-metabolism-and-toxicity-in-human
#17
Keigo Konishi, Tatsuki Fukami, Saki Gotoh, Miki Nakajima
Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s)...
June 9, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28604124/test-systems-in-drug-discovery-for-hazard-identification-and-risk-assessment-of-human-drug-induced-liver-injury
#18
Richard J Weaver, Catherine Betts, Eric A G Blomme, Helga H J Gerets, Klaus Gjervig Jensen, Philip G Hewitt, Satu Juhila, Gilles Labbe, Michael J Liguori, Natalie Mesens, Monday O Ogese, Mikael Persson, Jan Snoeys, James L Stevens, Tracy Walker, B Kevin Park
Introduction The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities...
June 12, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28603418/vesicular-melatonin-efficiently-downregulates-sodium-fluoride-induced-rat-hepato-and-broncho-tnf-%C3%AE-tgf-%C3%AE-expressions-and-associated-oxidative-injury-a-comparative-study-of-liposomal-and-nanoencapsulated-forms
#19
Suvomoy Sana, Swarupa Ghosh, Nirmalendu Das, Sibani Sarkar, Ardhendu Kumar Mandal
The importance of fluoride as a natural and industrial toxicant is recognized worldwide. We evaluated the regulating role and biological effect of vesicular (liposomal and nanoencapsulated) melatonin (N-acetyl-5-methoxytryptamine) for drug delivery and controlled release on the depletion of inflammatory mediators, as well as oxidative damage in sodium fluoride (NaF)-treated lungs and liver. Hepatic and bronchial damage was induced in Swiss albino rats with a single acute ingestion of NaF (48 mg/kg body weight, oral gavage)...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28603098/comparison-of-efficacy-of-folic-acid-and-silymarin-in-the-management-of-antiepileptic-drug-induced-liver-injury-a-randomized-clinical-trial
#20
Masoumeh Asgarshirazi, Mamak Shariat, Mahdi Sheikh
BACKGROUND: Liver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries (DILI) in children. Although withdrawal of the causative agent is the only proved treatment for DILI, in some clinical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with antioxidant actions for the management of DILI. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy...
June 2017: Hepatobiliary & Pancreatic Diseases International: HBPD INT
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