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Drug-induced hepatotoxicity

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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/28627888/investigation-of-drug-induced-hepatotoxicity-and-its-remediation-pathway-with-reaction-based-fluorescent-probes
#2
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/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
#3
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
#4
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/28614776/nonsteroidal-anti-inflammatory-drugs-induced-failure-of-lower-esophageal-and-pyloric-sphincter-and-counteraction-of-sphincters-failure-with-stable-gatric-pentadecapeptide-bpc-157-in-rats
#5
S Vitaic, M Stupnisek, D Drmic, L Bauk, A Kokot, R Klicek, A Vcev, K Luetic, S Seiwerth, P Sikiric
The sphincters failure is a part of NSAIDs-toxicity that can be accordingly counteracted. We used a safe stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), LD1 not achieved, since successful in inflammatory bowel disease trials, and counteracts esophagitis, sphincters failure, gastrointestinal ulcer and skin ulcer, external and internal fistulas in rats, and particularly counteracts all NSAIDs-lesions. We assessed lower esophageal sphincter and pyloric sphincter pressure (cmH2O) in rats treated with various NSAIDs regimens, at corresponding time points, known to produce stomach, small intestine lesions, hepatotoxicity and encephalopathy...
April 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28612260/utility-of-spherical-human-liver-microtissues-for-prediction-of-clinical-drug-induced-liver-injury
#6
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
#7
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/28604124/test-systems-in-drug-discovery-for-hazard-identification-and-risk-assessment-of-human-drug-induced-liver-injury
#8
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/28603092/crosstalk-of-liver-immune-cells-and-cell-death-mechanisms-in-different-murine-models-of-liver-injury-and-its-clinical-relevance
#9
Hilal Ahmad Khan, Muhammad Zishan Ahmad, Junaid Ali Khan, Muhammad Imran Arshad
BACKGROUND: Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions...
June 2017: Hepatobiliary & Pancreatic Diseases International: HBPD INT
https://www.readbyqxmd.com/read/28598048/hepatotoxicity-in-hiv-patients-an-observational-study-in-patients-from-tertiary-care-centre-of-western-india
#10
Smrati Bajpai, Kavita Joshi
OBJECTIVE: HIV AIDS has currently become a chronic manageable condition with HAART, but with its chronicity and lifelong therapy currently the adverse drug reactions to these drugs are the main concern for any treating physician. Hepatotoxicity is one of the prime concerns of any physician managing HIV patients. We observe a number of patients reporting hepatotoxicity in our cohort and this had great impact on the efficacy and intake of the HAART drugs, this led us to explore this area and to find out the prevalence and etiologies in our cohort...
May 2017: Journal of the Association of Physicians of India
https://www.readbyqxmd.com/read/28580117/two-photon-fluorescent-probe-for-revealing-drug-induced-hepatotoxicity-via-mapping-fluctuation-of-peroxynitrite
#11
Yong Li, Xilei Xie, Xiu'e Yang, Mengmeng Li, Xiaoyun Jiao, Yuhui Sun, Xu Wang, Bo Tang
Drug-induced injury has attracted increasing attention in public health issues. Among them, hepatotoxicity has been regarded as the leading clinical problem caused by drug toxicity. However, owing to the complexity of the involved pathophysiological mechanisms and the lack of noninvasive, straightforward, and real-time tools, drug-induced hepatotoxicity has rarely been predicted satisfactorily. In this paper, by utilizing the reactive species peroxynitrite (ONOO(-)) as a biomarker, we present a two-photon fluorescent probe, TP-KA, holding rapid response, high specificity and sensitivity towards ONOO(-), to investigate drug (acetaminophen and tolcapone)-related liver injury and the remediate effect of N-acetyl cysteine (NAC)...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28578215/effects-of-agomelatine-on-pentylenetetrazole-induced-kindling-kindling-associated-oxidative-stress-and-behavioral-despair-in-mice-and-modulation-of-its-actions-by-luzindole-and-1-m-chlorophenyl-piperazine
#12
M Suhaib Azim, Nidhi B Agarwal, Divya Vohora
In view of well-evidenced antiepileptic effects of melatonin and few reports of anticonvulsant action of agomelatine, the present study investigated whether agomelatine protects against pentylenetetrazole (PTZ)-induced kindling in mice and kindling-associated oxidative stress, depression, and impairment of spatial memory. In order to explore whether effects are mediated by melatonergic or serotonergic mechanisms, 1-(m-chlorophenyl) piperazine (mCPP), selective 5HT2c receptor agonist and luzindole, melatonergic receptor antagonist, were taken as pharmacological tools...
June 1, 2017: Epilepsy & Behavior: E&B
https://www.readbyqxmd.com/read/28577870/mitochondria-as-the-target-for-the-modulatory-effect-of-curcumin-in-oxaliplatin-induced-toxicity-in-isolated-rat-liver-mitochondria
#13
Mohammad Waseem, Suhel Parvez, Heena Tabassum
BACKGROUND AND AIMS: To explore hepatoprotective action of curcumin (CMN, a bioflavonoid) on oxaliplatin (Oxa)-triggered mitochondrial oxidative stress and respiratory chain complexes in liver of rats. Oxa is a ubiquitously utilized platinum-based chemotherapeutic agent commonly used for the treatment of colorectal cancer. Mitochondria have recently emerged as targets for anticancer drugs in several kinds of toxicity including hepatotoxicity that can lead to neoplastic disease. There is a dearth of evidence involving the role of mitochondria in mediating Oxa-evoked hepatotoxicity and its underlying mechanism is still debatable...
January 2017: Archives of Medical Research
https://www.readbyqxmd.com/read/28577513/synergistic-protective-effect-of-picrorhiza-with-honey-in-acetaminophen-induced-hepatic-injury
#14
Prashant Gupta, Alok Tripathi, Tripti Agrawal, Chandradeo Narayan, B M Singh, Mohan Kumar, Arvind Kumar
Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations...
August 2016: Indian Journal of Experimental Biology
https://www.readbyqxmd.com/read/28574284/a-critical-review-on-hepatoprotective-effects-of-bioactive-food-components
#15
Kumar Ganesan, Muthukumaran Jayachandran, Baojun Xu
BACKGROUND: Bioactive food components are nonessential biomolecules, which help to give beneficial effects to human being against several diseases. Natural bioactive food components derived from plants and animals, such as phytosterols, carotenoids, polyphenols and fatty acids, have been proposed as valuable substitutions for anticipation and management of hepatotoxic effects and its chronic complications based on in vitro and in vivo studies. OBJECTIVES OF THE STUDY: To summarize drugs and chemical-induced hepatotoxicity and review how various bioactive food components attenuate the hepatotoxicity via cellular mechanisms...
June 2, 2017: Critical Reviews in Food Science and Nutrition
https://www.readbyqxmd.com/read/28573237/protective-effect-of-moringa-peregrina-leaves-extract-on-acetaminophen-induced-liver-toxicity-in-albino-rats
#16
Samy Abdelfatah Abdel Azim, Mohamed Taha Abdelrahem, Mostafa Mohamed Said, Alshaimaa Khattab
BACKGROUND: Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. MATERIALS AND METHODS: Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks...
2017: African Journal of Traditional, Complementary, and Alternative Medicines: AJTCAM
https://www.readbyqxmd.com/read/28560522/2-hydroxy-4-methoxy-benzoic-acid-attenuates-the-carbon-tetra-chloride-induced-hepatotoxicity-and-its-lipid-abnormalities-in-rats-via-anti-inflammatory-and-antioxidant-mechanism
#17
Ghedeir M Alshammari, Aristatile Balakrishnan, Thirunavukkarasu Chinnasamy
BACKGROUND AND AIM: Liver inflammation stimulates various inflammatory cytokines and initiates injury through oxidative stress. The aim of this study was to curtaile the liver injury through natural principles such as 2-hydroxy-4-methoxy benzoic acid (HMBA). METHODS: The current study examines the hepatoprotective and lipid lowering effect of HMBA against carbon tetra chloride (CCl4)-mediated liver toxicity in male Wistar rats. RESULTS: The hepatoprotective effects of HMBA against CCl4-induced liver damage, were evident from low serum transaminases activities, reduced hepatic lipid peroxidation and collagen content, restoration of total glutathione, and recouping of the inflammatory cytokines, such as TNF-α, IL-1β, IL-10, and IL-6 levels...
May 30, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28558354/anthocyanin-rich-riceberry-bran-extract-attenuates-gentamicin-induced-hepatotoxicity-by-reducing-oxidative-stress-inflammation-and-apoptosis-in-rats
#18
Phatchawan Arjinajarn, Nuttawud Chueakula, Anchalee Pongchaidecha, Krit Jaikumkao, Varanuj Chatsudthipong, Sugunya Mahatheeranont, Orranuch Norkaew, Nipon Chattipakorn, Anusorn Lungkaphin
Liver plays an important role in the detoxification and metabolic elimination of various drugs and harmful substances. The damaging effects on the liver tissue treated with gentamicin are multi-factorial and their mechanisms remain unclear. This study aimed to investigate the possible protective effects of anthocyanin-rich Riceberry bran extract on gentamicin-induced hepatotoxicity in rats. Riceberry bran extract was given by oral administration 30min before gentamicin injection for 15 consecutive days. Serum levels of liver marker enzymes, AST and ALT, were significantly elevated and the total serum protein level was markedly reduced in gentamicin-treated rats...
May 27, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28556920/ampk-activator-acadesine-fails-to-alleviate-isoniazid-caused-mitochondrial-instability-in-hepg2-cells
#19
Tian-Guang Zhang, Takashi Ikejima, Toshihiko Hayashi, Jun Zhao, Yi-Mei Wang, Shuang-Qing Peng
Isoniazid (INH) is a first-line antituberculosis drug that is adversely associated with hepatotoxicity. Recently, impairment of mitochondrial homeostasis involved in this side effect has been noticed. Mitochondrial homeostasis is achieved by the balance between the generation of functional mitochondria by biogenesis and elimination of dysfunctional mitochondria by autophagy. AMP-activated protein kinase (AMPK) can maintain mitochondrial stability through positive control of these two processes. In this study, we showed that AMPK activator acadesine (AICAR) alleviated INH-caused impairment of mitochondrial biogenesis by activation of silent information regulator two ortholog 1 (SIRT1)-peroxisome proliferator-activated receptor γ coactivator 1α (PGC1 α) pathway in HepG2 cells...
May 29, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/28555362/the-incidence-of-drug-and-herbal-and-dietary-supplement-induced-liver-injury-preliminary-findings-from-gastroenterologist-based-surveillance-in-the-population-of-the-state-of-delaware
#20
Maricruz Vega, Manisha Verma, David Beswick, Stephanie Bey, Jared Hossack, Nathan Merriman, Ashish Shah, Victor Navarro
BACKGROUND AND AIM: The population-based incidence rate of drug-induced liver injury (DILI) in the USA is not known. The Drug-Induced Liver Injury Network (DILIN) accrues cases of hepatotoxicity due to medications and herbal and dietary supplements (HDS) from limited geographical areas. The current analysis was an ancillary study of DILIN aimed at determining the annual incidence of DILI in the USA on a population basis, through surveillance in the state of Delaware. METHODS: At the outset of the study, there were 41 gastroenterologists in the state of Delaware and all agreed to participate in surveillance for DILI, which comprised active reporting of suspected cases to the DILIN...
May 29, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
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