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Drug-induced hepatotoxicity

Xin-Zhi Wang, Ru-Feng Xue, Shen-Ye Zhang, Ya-Ting Zheng, Lu-Yong Zhang, Zhen-Zhou Jiang
Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers...
July 16, 2018: Acta Pharmacologica Sinica
Milad Iranshahy, Mehrdad Iranshahi, Seyed Reza Abtahi, Gholamreza Karimi
Internal metabolism and environmental toxicant exposure can be caused to generate reactive oxygen species in human organelles which lead to oxidative stress. The nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper (bZip) transcription factor, controls the expression of antioxidant response element (ARE)-dependent genes to regulate cellular resistance to oxidants. Nrf2 is an essential factor for hepatoprotection against drugs and xenobiotics. The key role of Nrf2 in hepatoprotection has been highlighted since Nrf2 knockout mice showed high sensitivity to xenobiotic-induced hepatotoxicity...
July 14, 2018: Food and Chemical Toxicology
Chun Yip Chan, Alex Cheow Khoon Soh, Dorinda Yan Qin Kioh, Jianguo Li, Chandra Verma, Siew Kwan Koh, Roger Wilmer Beuerman, Lei Zhou, Eric Chun Yong Chan
Although covalent protein binding is established as the pivotal event underpinning acetaminophen (APAP) toxicity, its mechanistic details remain unclear. In this study, we demonstrated that APAP induces widespread protein glutathionylation in a time-, dose- and bioactivation-dependent manner in HepaRG cells. Proteo-metabonomic mapping provided evidence that APAP-induced glutathionylation resulted in functional deficits in energy metabolism, elevations in oxidative stress and cytosolic calcium, as well as mitochondrial dysfunction that correlate strongly with the well-established toxicity features of APAP...
July 13, 2018: Molecular & Cellular Proteomics: MCP
Sigal Kaplan, Birgit Ehlken, Xenia Hamann
OBJECTIVE: In response to safety concerns, risk minimization measures (RMM) for flupirtine were implemented in Europe in 2013 to reduce hepatotoxicity risk. This study aims to characterize compliance and prescribing practices of flupirtine before and after RMM implementation. RESEARCH DESIGN AND METHODS: A retrospective pre-post design cohort study was conducted in the outpatient setting using a longitudinal electronic medical record database in Germany. The study population included patients who initiated flupirtine...
July 11, 2018: Current Medical Research and Opinion
Fenfen Li, He Li, Shasha Luo, Yantao Ran, Xiaoqian Xie, Yale Wang, Ming Zheng, Mengzhen Wang, Zeyue Zhao, Xiaotian Li
OBJECTIVE: Methotrexate is one of the most widely used disease-modifying anti-rheumatic drugs. The hepatotoxicity of methotrexate resulted in poor compliance with therapy. The current study was designed to analyse the combined therapy of andrographolide (AD) and methotrexate (MTX) for complete Freund's adjuvant (CFA)-induced arthritis, focusing on hepatoprotective effects, oxidative stress and arthritic-related cytokines. METHOD: Wistar rats were injected with CFA into the right hind paw...
July 4, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Neha Saini, Shikha Bakshi, Sadhna Sharma
Drug induced liver injury (DILI) is the prime cause of liver disfunction which may lead to mild non-specific symptoms to more severe signs like hepatitis, cholestasis, cirrhosis and jaundice. Not only the prescription medications, but the consumption of herbs and health supplements have also been reported to cause these adverse reactions resulting into high mortality rates and post marketing withdrawal of drugs. Due to the continuously increasing DILI incidences in recent years, robust prediction methods with high accuracy, specificity and sensitivity are of priority...
July 5, 2018: Toxicology Letters
Hongqiong Zhao, Zhihui Jiang, Xuemei Chang, Huiting Xue, Wumaierjiang Yahefu, Xiaoying Zhang
Acetaminophen (APAP) overdose is the principal cause of drug-induced acute liver failure. 4-hydroxyphenylacetic acid (4-HPA), a major microbiota-derived metabolite of polyphenols, is involved in the antioxidative action. This study seeks to investigate the ability of 4-HPA to protect against APAP-induced hepatotoxicity, as well as the putative mechanisms involved. Mice were treated with 4-HPA (6, 12, or 25 mg/kg) for 3 days, 1 h after the last administration of 4-HPA, a single dose of APAP was intraperitoneally infused for mice...
2018: Frontiers in Pharmacology
Takeshi Toyoda, Young-Man Cho, Jun-Ichi Akagi, Yasuko Mizuta, Kohei Matsushita, Akiyoshi Nishikawa, Katsumi Imaida, Kumiko Ogawa
Although obesity is increasing worldwide, experimental studies examining the possible association between obesity and susceptibility to chemical toxicity are limited. In the present study, we performed a 13-week toxicity study for acetaminophen (APAP), a well-known drug that exhibits hepatotoxicity as an adverse effect, using an obese rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 80, 253, 800, 2,530, or 8,000 ppm APAP in the diet for 13 weeks...
2018: Journal of Toxicological Sciences
Huaqiao Tang, Nana Long, Min Dai, Lin Lin, Jianlong Li, Fenghui Sun, Lijuan Guo
CONTEXT: Citral is used as a potential natural treatment for various infectious diseases. OBJECTIVE: To examine the effect of citral on the mRNA expression and activities of cytochrome P450 (CYP450) enzymes and establish the relationship between citral-induced liver injury and oxidative stress. MATERIALS AND METHODS: ICR mice were randomly divided into citral (20, 200, and 2000 mg/kglow), Tween-80, and control groups (0.9% saline), 10 mice in each group...
December 2018: Pharmaceutical Biology
Mohammad Hosein Farzaei, Mahdi Zobeiri, Fatemeh Parvizi, Fardous F El-Senduny, Ilias Marmouzi, Ericsson Coy-Barrera, Rozita Naseri, Seyed Mohammad Nabavi, Roja Rahimi, Mohammad Abdollahi
Oxidative stress has been considered a key causing factor of liver damage induced by a variety of agents, including alcohol, drugs, viral infections, environmental pollutants and dietary components, which in turn results in progression of liver injury, non-alcoholic steatohepatitis, non-alcoholic liver disease, liver fibrosis and cirrhosis. During the past 30 years and even after the major progress in the liver disease management, millions of people worldwide still suffer from an acute or chronic liver condition...
July 1, 2018: Nutrients
Sophie Billioti de Gage, Cédric Collin, Thien Le-Tri, Antoine Pariente, Bernard Bégaud, Hélène Verdoux, Rosemary Dray-Spira, Mahmoud Zureik
BACKGROUND: Hepatotoxicity may be a concern when prescribing antidepressants. Nevertheless, this risk remains poorly understood for serotonin and noradrenaline reuptake inhibitors (SNRIs: venlafaxine, milnacipran, duloxetine) and 'other antidepressants' (mianserin, mirtazapine, tianeptine and agomelatine), particularly in comparison with selective serotonin reuptake inhibitors (SSRIs: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, escitalopram), which are by far the most commonly prescribed antidepressants...
June 29, 2018: CNS Drugs
Chih-Ju Lin, Sheng-Lin Lee, Hsuan-Shu Lee, Chen-Yuan Dong
We used intravital multiphoton microscopy to study the recovery of hepatobiliary metabolism following carbon tetrachloride (CCl4) induced hepatotoxicity in mice. The acquired images were processed by a first order kinetic model to generate rate constant resolved images of the mouse liver. We found that with progression of hepatotoxicity, the spatial gradient of hepatic function disappeared. A CCl4-induced damage mechanism involves the compromise of membrane functions, resulting in accumulation of processed 6-carboxyfluorescein molecules...
June 2018: Journal of Biomedical Optics
Yong-Hoon Kim, Jung-Ran Noh, Jung Hwan Hwang, Kyoung-Shim Kim, Dong-Hee Choi, Jae-Hoon Kim, Sung Je Moon, Ji Hyun Choi, Yann Hérault, Tae Geol Lee, Hueng-Sik Choi, Chul-Ho Lee
Acetaminophen (APAP) overdose is a leading cause of drug-induced acute liver failure. Prolonged c-Jun N-terminal kinase (JNK) activation plays a central role in APAP-induced liver injury; however, growth arrest and DNA damage-inducible 45 beta (GADD45β) is known to inhibit JNK phosphorylation. The orphan nuclear receptor small heterodimer partner (SHP, NR0B2) acts as a transcriptional co-repressor of various genes. The aim of the present study was to investigate the role of SHP in APAP-evoked hepatotoxicity...
June 25, 2018: Archives of Toxicology
Jamil M Shah, Kyawzaw Lin, Denzil Etienne, Madhavi Reddy, Yingxian Liu
Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the digestive tract. The clinical behavior of GISTs varies greatly, has extended follow-up, and almost all of the tumors have malignant potential. The introduction of imatinib has led to extraordinary improvements in the treatment of individuals with GISTs (as well as those with Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL)). However, there have been notable postmarketing reports of adverse drug reactions of hepatotoxicity with the use of imatinib...
April 24, 2018: Curēus
Ling-Yu Ruan, Jun-Ting Fan, Wei Hong, He Zhao, Ming-Hui Li, Lei Jiang, Yong-Hong Fu, Yue-Xiao Xing, Cheng Chen, Jun-Song Wang
Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1 H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting...
June 21, 2018: Toxicology Letters
Andrea Fisler, Tobias Breidthardt, Nadine Schmidlin, Helmut Hopfer, Michael Dickenmann, Katrin König, Patricia Hirt-Minkowski
Renal dysfunction in the setting of cholestatic liver disease is multifactorial but most often due to decreased kidney perfusion from intravascular volume depletion, acute tubular injury/necrosis, and hepatorenal syndrome. Drug-induced hepatotoxicity may be associated with a cholestatic injury pattern. We report a case of a 56-year-old man with a diagnosis of bile cast nephropathy, as a complication of drug-induced severe hyperbilirubinemia due to the abuse of intramuscular anabolic steroids bought on the internet to increase muscular mass for bodybuilding training...
May 2018: Case Reports in Nephrology and Dialysis
Chang Chen, Jian Gao, Tie-Shan Wang, Cong Guo, Yu-Jing Yan, Chao-Yi Mao, Li-Wei Gu, Yang Yang, Zhong-Feng Li, An Liu
Emodin is a natural anthraquinone derivative that is present in various herbal preparations. The pharmacological effects of emodin include anticancer, hepatoprotective, anti-inflammatory, antioxidant and even antimicrobial activities. However, emodin also has been reported to induce hepatotoxicity, nephrotoxicity, genotoxicity and reproductive toxicity. The mechanism of emodin's adverse effects is complicated and currently not well understood. This study aimed to establish a cell metabonomic method to investigate the toxicity of emodin and explore its potential mechanism and relevant targets...
June 20, 2018: Scientific Reports
Dae-Seop Shin, Hyewon Seo, Jung Yoon Yang, Jeongmin Joo, So Hee Im, Seong Soon Kim, Sang Kyum Kim, Myung Ae Bae
Predicting drug-drug interactions (DDIs) is an important step during drug development to avoid unexpected side effects. Cytochrome P450 (CYP) 3A4 is the most abundant human hepatic phase I enzyme, which metabolizes >50% of therapeutic drugs. Therefore, it is essential to test the potential of a drug candidate to induce CYP3A4 expression or inhibit its activity. Recently, 3-dimensional (3-D) mammalian cell culture models have been adopted in drug discovery research to assess toxicity, DDIs, and pharmacokinetics...
January 1, 2018: International Journal of Toxicology
Céline Parmentier, Delilah F G Hendriks, Bruno Heyd, Philippe Bachellier, Magnus Ingelman-Sundberg, Lysiane Richert
Cholestasis represents a major subtype of drug-induced liver injury and novel preclinical models for its prediction are needed. Here we used primary human hepatocytes (PHH) from different donors in 2D-sandwich (2D-sw) and/or 3D-spheroid cultures to study inter-individual differences in response towards cholestatic hepatotoxins after short-term (48-72 h) and long-term repeated exposures (14 days). Cholestatic liabilities were determined by comparing cell viability upon exposure to the highest non-cytotoxic drug concentration in the presence and absence of a non-cytotoxic concentrated bile acid (BA) mixture...
June 15, 2018: Toxicology Letters
Richa Shrivastava, Shruti Trivedi, Pankaj Kumar Singh, Mohammad Asif, Manish Kumar Chourasia, Amit Khanna, Smrati Bhadauria
Breast cancer is most frequently diagnosed cancer and fifth leading cause of death in women. About 20-30% of all breast cancers overexpress HER2/neu receptors. Lapatinib is a dual tyrosin kinase inhibitor of EGFR and HER2. It exhibits its anticancer effect via blocking intracellular domain of HER2 receptor in breast cancer. Lapatinib belongs to class II of BSC classification due to its poor solubility restricting its clinical application. Due to presence of HER2 receptor on cardiomyocytes, it is associated with generation of cardiotoxicity...
June 13, 2018: Biochemical and Biophysical Research Communications
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