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Drug-induced hepatotoxicity

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https://www.readbyqxmd.com/read/28527127/evaluation-of-heparg-cells-for-the-assessment-of-indirect-drug-induced-hepatotoxicity-using-inh-as-a-model-substance
#1
Anika Mann, Thomas Pelz, Knut Rennert, Alexander Mosig, Michael Decker, Amelie Lupp
HepaRG cells are widely used as an in vitro model to assess drug-induced hepatotoxicity. However, only few studies exist so far regarding their suitability to detect the effects of drugs requiring a preceding activation via the cytochrome P450 (CYP) system. A prototypic substance is the anti-tuberculosis agent INH, which is metabolized into N-acetylhydrazine, which then triggers hepatotoxicity. Therefore, the aim of the present study was to test if this effect can also be detected in HepaRG cells and if it can be counteracted by the known hepatoprotectant silibinin...
May 19, 2017: Human Cell
https://www.readbyqxmd.com/read/28521054/in-silico-prediction-of-drug-induced-liver-injury-based-on-adverse-drug-reaction-reports
#2
Xiang-Wei Zhu, Shao-Jing Li
Drug-induced liver injury (DILI) is a major cause of drug attrition. Currently existing Quantitative Structure-Activity Relationship (QSAR) models have limited predictive capabilities for DILI. Furthermore, their practical applications were limited by lack of new hepatotoxicity data. In this study, we first collected and curated a novel set of 122 DILI-positive and 932 DILI-negative drugs from online adverse drug reports using proportional reporting ratios as the signal detection method. Second, three strategies (under-sampling the majority class, synthetic minority over-sampling technique, and adjusting decision threshold approach) were employed to develop predictive classification models to cope with the unbalanced dataset...
May 17, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28505368/farnesoid-x-receptor-protects-against-low-dose-carbon-tetrachloride-induced-liver-injury-through-the-taurocholate-jnk-pathway
#3
Shogo Takahashi, Naoki Tanaka, Srujana Golla, Tatsuki Fukami, Kristopher W Krausz, Marianne A Polunas, Blair C Weig, Yusuke Masuo, Cen Xie, Changtao Jiang, Frank J Gonzalez
Hepatotoxicity is of major concern for humans exposed to industrial chemicals and drugs. Disruption of farnesoid X receptor (FXR), a master regulator of bile acid (BA) metabolism, enhanced the sensitivity to liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. In this study, the interconnection between BA metabolism, FXR, and chemically-induced hepatotoxicity was investigated using metabolomics, Fxr-null mice and hepatocytes, and adenovirus. A single low-dose intraperitoneal injection of carbon tetrachloride (CCl4), an inducer of acute hepatitis in mice, resulted in more severe hepatocyte damage and higher induction of pro-inflammatory mediators, such as chemokine (C-C motif) ligand 2 (Ccl2), in Fxr-null mice...
May 15, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28499383/nintedanib-antiangiogenic-inhibitor-effectiveness-in-delaying-adenocarcinoma-progression-in-transgenic-adenocarcinoma-of-the-mouse-prostate-tramp
#4
Raquel Frenedoso da Silva, Ellen Nogueira-Pangrazi, Larissa Akemi Kido, Fabio Montico, Sarah Arana, Dileep Kumar, Komal Raina, Rajesh Agarwal, Valéria Helena Alves Cagnon
BACKGROUND: In recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model...
May 12, 2017: Journal of Biomedical Science
https://www.readbyqxmd.com/read/28496041/a-rapid-mitochondrial-toxicity-assay-utilizing-rapidly-changing-cell-energy-metabolism
#5
Yosuke Sanuki, Tetsuro Araki, Osamu Nakazono, Kazuyuki Tsurui
Drug-induced liver injury is a major cause of safety-related drug-marketing withdrawals. Several drugs have been reported to disrupt mitochondrial function, resulting in hepatotoxicity. The development of a simple and effective in vitro assay to identify the potential for mitochondrial toxicity is thus desired to minimize the risk of causing hepatotoxicity and subsequent drug withdrawal. An in vitro test method called the "glucose-galactose" assay is often used in drug development but requires prior-culture of cells over several passages for mitochondrial adaptation, thereby restricting use of the assay...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28486596/troglitazone-inhibits-bile-acid-amidation-a-possible-risk-factor-for-liver-injury
#6
Eiichiro Ogimura, Tetsuya Nakagawa, Jiro Deguchi, Shuichi Sekine, Kousei Ito, Kiyoko Bando
Troglitazone and pioglitazone were developed as thiazolidinedione-type anti-diabetes drugs, but only troglitazone was withdrawn from the markets due to severe liver injury. As both troglitazone and its sulfate metabolite are strong inhibitors of the bile salt export pump (BSEP), troglitazone-induced bile acid (BA) retention is thought to be one of the underlying mechanisms of liver injury. However, pioglitazone is also a strong BSEP inhibitor, indicating other mechanisms may also be involved in troglitazone-induced BA retention...
May 9, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28486401/drug-induced-liver-injury-cascade-of-events-leading-to-cell-death-apoptosis-or-necrosis
#7
REVIEW
Andrea Iorga, Lily Dara, Neil Kaplowitz
Drug-induced liver injury (DILI) can broadly be divided into predictable and dose dependent such as acetaminophen (APAP) and unpredictable or idiosyncratic DILI (IDILI). Liver injury from drug hepatotoxicity (whether idiosyncratic or predictable) results in hepatocyte cell death and inflammation. The cascade of events leading to DILI and the cell death subroutine (apoptosis or necrosis) of the cell depend largely on the culprit drug. Direct toxins to hepatocytes likely induce oxidative organelle stress (such as endoplasmic reticulum (ER) and mitochondrial stress) leading to necrosis or apoptosis, while cell death in idiosyncratic DILI (IDILI) is usually the result of engagement of the innate and adaptive immune system (likely apoptotic), involving death receptors (DR)...
May 9, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28479956/a-single-zidovudine-azt-administration-delays-hepatic-cell-proliferation-by-altering-oxidative-state-in-the-regenerating-rat-liver
#8
Armando Butanda-Ochoa, Diego Rolando Hernández-Espinosa, Marisela Olguín-Martínez, Lourdes Sánchez-Sevilla, Mario R Rodríguez, Benito Chávez-Rentería, Alberto Aranda-Fraustro, Rolando Hernández-Muñoz
The 3'-azido-3'-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH)...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28479099/protective-effect-of-chlorogenic-acid-against-methotrexate-induced-oxidative-stress-inflammation-and-apoptosis-in-rat-liver-an-experimental-approach
#9
Nemat Ali, Summya Rashid, Sana Nafees, Syed Kazim Hasan, Ayaz Shahid, Ferial Majed, Sarwat Sultana
Methotrexate (MTX) is a drug which is used to treat different types of cancers but hepatotoxicity limits its clinical use. Chlorogenic acid (CGA) is one of the most abundant naturally occurring polyphenols in the human diet. Here, we assessed the effect of CGA against MTX-induced hepatotoxicity and investigated the underlying possible mechanisms in Wistar Rats. Rats were pre-treated with CGA (50 or 100 mg kg/b.w) and administered a single dose of MTX (20 mg/kg, b.w.). MTX caused hepatotoxicity as evidenced by significant increase in serum toxicity markers, histopathological changes...
May 4, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28476244/imaging-of-hepatic-toxicity-of-systemic-therapy-in-a-tertiary-cancer-centre-chemotherapy-haematopoietic-stem-cell-transplantation-molecular-targeted-therapies-and-immune-checkpoint-inhibitors
#10
REVIEW
F Alessandrino, S H Tirumani, K M Krajewski, A B Shinagare, J P Jagannathan, N H Ramaiya, D N Di Salvo
The purpose of this review is to familiarise radiologists with the spectrum of hepatic toxicity seen in the oncology setting, in view of the different systemic therapies used in cancer patients. Drug-induced liver injury can manifest in various forms, and anti-neoplastic agents are associated with different types of hepatotoxicity. Although chemotherapy-induced liver injury can present as hepatitis, steatosis, sinusoidal obstruction syndrome, and chronic parenchymal damages, molecular targeted therapy-associated liver toxicity ranges from mild liver function test elevation to fulminant life-threatening acute liver failure...
May 2, 2017: Clinical Radiology
https://www.readbyqxmd.com/read/28474630/genetic-polymorphisms-of-n-acetyltransferase-2-susceptibility-to-antituberculosis-drug-induced-hepatotoxicity
#11
Surendra K Sharma, Brajesh Kumar Jha, Abhishek Sharma, V Sreenivas, Vishwanath Upadhyay, Chandrita Jaisinghani, Rohit Singla, Hemant Kumar Mishra, Manish Soneja
BACKGROUND & OBJECTIVES: The N-acetyltransferase 2 (NAT2) gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH). METHODS: In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs...
December 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/28473992/hepatotoxicity-of-antimycotics-used-for-invasive-fungal-infections-in-vitro-results
#12
Sandra Doß, Heike Potschka, Fanny Doß, Steffen Mitzner, Martin Sauer
Purpose. Drug-induced liver injury (DILI) is the most common cause of liver injury and a serious clinical problem; antimycotics are involved in approximately 3% of all DILI cases. The hepatotoxicity of many drugs, including the antimycotics, is poorly screened in human models. Methods. In a standardized assay the cytotoxicity on hepatocytes of different concentrations (Cmax, 5x Cmax, and 10x Cmax) of the antimycotics used for systemic infections was tested. Anidulafungin (ANI), liposomal amphotericerin B (L-AmB), caspofungin (CASPO), fluconazole (FLUCO), and voriconazole (VORI) were incubated with HepG2/C3A cells...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28470665/pentamidine-blocks-hepatotoxic-injury-in-mice
#13
Enpeng Zhao, Ghulam Ilyas, Francesca Cingolani, Jae Ho Choi, François Ravenelle, Kathryn E Tanaka, Mark J Czaja
Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury...
May 3, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28467181/pre-clinical-and-clinical-investigations-of-metabolic-zonation-in-liver-diseases-the-potential-of-microphysiology-systems
#14
Alejandro Soto-Gutierrez, Albert Gough, Lawrence A Vernetti, D L Taylor, Satdarshan P Monga
The establishment of metabolic zonation within a hepatic lobule ascribes specific functions to hepatocytes based on unique, location-dependent gene expression patterns. Recently, there have been significant developments in the field of metabolic liver zonation. A little over a decade ago, the role of β-catenin signaling was identified as a key regulator of gene expression and function in pericentral hepatocytes. Since then, additional molecules have been identified that regulate the pattern of Wnt/β-catenin signaling within a lobule and determine gene expression and function in other hepatic zones...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28464763/sporadic-porphyria-in-a-patient-with-stage-ii-melanoma-treated-with-interferon-%C3%AE
#15
Valerie Reymann, Celine Girard, Olivier Dereure, Bernard Guillot, Aurélie Du Thanh
Porphyria cutanea tarda (PCT) is the most common form of human porphyria, due to reduced activity of uroporphyrinogen decarboxylase (UROD). There are many factors which can trigger PCT such as viral infections, excessive alcohol intake, iron overload, hepatotoxic drugs and hepatic tumours. Drug induced PCT is well documented but PCT induced by interferon α has rarely been described and only in cases of Hepatitis C Virus (HCV) infection or haematological malignancies. Here, we report the first case of de novo PCT induced by adjuvant interferon α (IFNα) therapy in a patient with stage II melanoma...
May 2, 2017: Current Drug Safety
https://www.readbyqxmd.com/read/28463418/use-of-primary-rat-hepatocytes-for-prediction-of-drug-induced-mitochondrial-dysfunction
#16
Cong Liu, Shuichi Sekine, Binbin Song, Kousei Ito
Mitochondrial dysfunction plays a central role in drug-induced liver injury. To evaluate drug-induced mitochondrial impairment, several isolated mitochondria- or cell line-based assays have been reported. Among them, culturing HepG2 cells in galactose provides a remarkable method to assess mitochondrial toxicity by activating mitochondrial aerobic respiration. We applied this assay to primary rat hepatocytes by culturing cells in galactose and hyperoxia to enhance the evaluation of metabolism-related drug-induced mitochondrial toxicity...
May 2, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28463417/a-multi-parametric-fluorescent-assay-for-the-screening-and-mechanistic-study-of-drug-induced-steatosis-in-liver-cells-in-culture
#17
Laia Tolosa, M José Gómez-Lechón, M Teresa Donato
Human hepatic cells have been used for drug safety risk evaluations throughout early development phases. They provide rapid, cost-effective early feedback to identify drug candidates with potential hepatotoxicity. This unit presents a cell-based assay to evaluate the risk of liver damage associated with steatogenic drugs. Detailed protocols for cell exposure to test compounds and for the assessment of steatosis-related cell parameters (intracellular lipid content, reactive oxygen species production, mitochondrial impairment, and cell death) are provided...
May 2, 2017: Current Protocols in Toxicology
https://www.readbyqxmd.com/read/28462128/protection-of-hepatotoxicity-using-spondias-pinnata-by-prevention-of-ethanol-induced-oxidative-stress-dna-damage-and-altered-biochemical-markers-in-wistar-rats
#18
Shoaib Shadab Iqbal, Md Mujahid, Sayed Mohammad Kashif, Mohammad Khalid, Badruddeen, Muhammad Arif, Paramdeep Bagga, Juber Akhtar, Md Azizur Rahman
BACKGROUND: Traditional systems of medicine use herbal drugs for hepatoprotection. Thus, the study was designed to evaluate the hepatoprotective and antioxidant effects of Spondias pinnata bark extracts against ethanol-induced liver injury in Wistar rats. METHODS: Group I animals were treated with 1 mL/kg 0.3% carboxymethyl cellulose and Group II with 12 mL/kg 50% ethanol for 8 consecutive days. Groups III-VII animals were first treated with 400 mg/kg petroleum ether extract, chloroform extract, acetone extract (AE), ethanol extract (EE), and 100 mg/kg silymarin, and then 12 mL/kg 50% ethanol orally after 2 hours pretreatment each day for 8 consecutive days...
December 2016: Integr Med Res
https://www.readbyqxmd.com/read/28459937/cxcl16-deficiency-attenuates-acetaminophen-induced-hepatotoxicity-through-decreasing-hepatic-oxidative-stress-and-inflammation-in-mice
#19
Hong Wang, Yihui Shao, Saisai Zhang, Anqi Xie, Yanna Ye, Lihua Shi, Leigang Jin, Xuebo Pan, Zhuofeng Lin, Xiaokun Li, Shulin Yang
Chemokine C-X-C ligand 16 (CXCL16), a single-pass Type I membrane protein belonging to the CXC chemokine family, is related to the inflammatory response in liver injury. In present study, we investigated the pathophysiological role of CXCL16, a unique membrane-bound chemokine, in acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were injected with APAP, and blood and tissue samples were harvested at different time points. The serum high-mobility group box 1 and CXCL16 levels were quantified by sandwich immunoassays...
April 28, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28456008/donor-dependent-and-other-nondefined-factors-have-greater-influence-on-the-hepatic-phenotype-than-the-starting-cell-type-in-induced-pluripotent-stem-cell-derived-hepatocyte-like-cells
#20
James A Heslop, Richard Kia, Christopher S Pridgeon, Rowena L Sison-Young, Triantafillos Liloglou, Mohamed Elmasry, Stephen W Fenwick, John S Mills, Neil R Kitteringham, Chris E Goldring, Bong K Park
Drug-induced liver injury is the greatest cause of post-marketing drug withdrawal; therefore, substantial resources are directed toward triaging potentially dangerous new compounds at all stages of drug development. One of the major factors preventing effective screening of new compounds is the lack of a predictive in vitro model of hepatotoxicity. Primary human hepatocytes offer a metabolically relevant model for which the molecular initiating events of hepatotoxicity can be examined; however, these cells vary greatly between donors and dedifferentiate rapidly in culture...
May 2017: Stem Cells Translational Medicine
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