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Drug-induced hepatotoxicity

Nora Freyer, Selina Greuel, Fanny Knöspel, Florian Gerstmann, Lisa Storch, Georg Damm, Daniel Seehofer, Jennifer Foster Harris, Rashi Iyer, Frank Schubert, Katrin Zeilinger
The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0...
March 15, 2018: Bioengineering
Peng Sun, Jing-Jie Zhu, Ting Wang, Qi Huang, Yu-Ren Zhou, Bang-Wei Yu, Hua-Liang Jiang, He-Yao Wang
As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD)-induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group...
March 8, 2018: Biochimica et Biophysica Acta
Michael Schloss, Daniel Becak, Sebastian T Tosto, Arash Velayati
BACKGROUND Levofloxacin covers a broad spectrum of pathogens and is readily prescribed by clinicians. Hepatotoxicity is a known but unusual complication of levofloxacin use. Here, we present a case of severe transaminitis caused by levofloxacin. CASE REPORT A young man in his thirties with a history of asthma, chronic alcoholism, methamphetamine intravenous drug abuse (IVDA), and non-compliant insulin-dependent diabetes mellitus (IDDM) presented to an emergency department with suicidal ideation. Vital signs were stable and the patient was noted to have cellulitis of the right forearm, for which cultures were drawn, and he received IV clindamycin...
March 10, 2018: American Journal of Case Reports
Alamgeer, Zain Nasir, Muhammad Naeem Qaisar, Ambreen Malik Uttra, Haseeb Ahsan, Kifayat Ullah Khan, Ikram Ullah Khan, Muhamamd Saleem, Khadijai, Hira Asif, Amber Sharif, Waqas Younis, Huma Naz
Hepatic diseases are becoming common day by day and pose serious health threats to the life of humans. In order to treat these diseases, the attention of man is diverting towards herbal drugs, which are much safer and cost effective than synthetic drugs. The aim of present study was to investigate hepatoprotective activity of methanolic extract of Melilomus officinalis against paracetamol and carbon tetrachloride induced hepatic damage. Melilotus officinalis at selected oral doses of 50 mg/kg and 100 mg/kg showed significant hepatoprotective effects by decreasing the levels of serum marker enzymes such as total bilirubin, SGOT, SGPT, ALP, albumin and total protein, when compared with standard drug (silymarin) and negative control...
May 2017: Acta Poloniae Pharmaceutica
Clement Bresteau, Sophie Prevot, Gabriel Perlemuter, Cosmin Voican
Drug-induced liver injury is the fourth most common cause of liver disease in industrialised countries. Methylprednisolone is often considered to be a treatment with a low hepatotoxicity. We report a case of methylprednisolone-induced liver injury in a 35-year-old woman. She was admitted to our department for acute liver injury 2 months after a treatment with high dose of methylprednisolone (1 g/day) for a multiple sclerosis relapse. No other cause of liver injury could be found (screening for hepatotropic viruses, autoimmune antibodies, ceruloplasmin, abdominal ultrasonography and liver biopsy)...
March 5, 2018: BMJ Case Reports
Ajeet Kumar Verma, Arti Yadav, Sarvendra Vikram Singh, Pratibha Mishra, Srikanta Kumar Rath
AIMS: Long-term treatment of Isoniazid (INH) in tuberculosis (TB) patients can lead to anti-tuberculosis drug-induced hepatotoxicity. To understand the mechanism of hepatotoxicity, an attempt has been made to elucidate the role of Nrf2, a transcription factor induced by oxidative stress, in INH induced apoptosis liver cancer cell lines. MATERIALS AND METHODS: Cytotoxicity was evaluated by MTT assay. Apoptosis and reactive oxygen species (ROS) generation was performed by flow cytometry...
February 27, 2018: Life Sciences
Isha Ranadive, Sonam Patel, Abhilasha Mhaske, Gowri Kumari Uggini, Isha Desai, Suresh Balakrishnan
Currently, scientists show keen interest in the drugs that inhibit multiple kinases, LDN193189, being an example. It combats certain cancers in vitro as well as in vivo, making it a prerequisite for researchers to study the toxic potential of this drug in animal models. As most of the drugs metabolized by liver cause hepatic injury, LDN193189-induced hepatotoxicity was examined using a teleost fish, Poecilia latipinna. As a prelude, calculation of LD50 showed a value of 95.22 mg/kg body weight and three doses were decided based on it for further evaluations...
March 2, 2018: Drug and Chemical Toxicology
Neha V Bhilare, Suneela S Dhaneshwar, Kakasaheb R Mahadik
Morphological and metabolic aberrations in the liver caused by long-term use of anti-tubercular agent isoniazid (INH) have been an issue of great concern in tuberculosis treatment. To resolve this issue, a novel hepatoprotective prodrug strategy was developed by combining the antioxidant property of phenolic acids with INH moiety for probable synergistic effect. In this work, INH was conjugated with phenolic antioxidants using Schotten-Baumann reaction through biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis and in vitro release studies were carried out using HPLC...
March 1, 2018: Drug Delivery and Translational Research
Meiyan Zhu, Akira Koibuchi, Hideyuki Ide, Hanae Morio, Minaka Shibuya, Atsuko Kamiichi, Akihito Tsubota, Naohiko Anzai, Hidetaka Akita, Kan Chiba, Tomomi Furihata
Liver sinusoidal endothelial cells (LSECs), which are specialized endothelial cells that line liver sinusoids, have been reported to participate in a variety of liver functions, such as blood macromolecule clearance and factor VIII production. In addition, LSECs play crucial roles in liver regeneration following acute liver injury, as well as the development and progression of liver diseases or drug-induced hepatotoxicity. However, the molecular mechanisms underlying their roles remain mostly unknown. Therefore, in order to contribute to the clarification of those mechanisms, herein we report on the development of a new immortalized human LSEC (HLSEC) line...
2018: Biological & Pharmaceutical Bulletin
Takuma Iguchi, Ken Sakurai, Satoshi Tamai, Kazuhiko Mori
Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point. We identified organ-specific miRNAs from cynomolgus monkeys by next-generation sequencing analysis, which revealed that miR-122 was only abundant in the liver, whereas miR-192 was abundant in the liver, stomach, intestines, and kidney...
January 2018: Journal of Toxicologic Pathology
Cyriac Abby Philips, Rajaguru Paramaguru, Adarsh K Joy, K L Antony, Philip Augustine
INTRODUCTION: Ayurvedic and herbal medicines (AHM) are known to cause varying degrees of drug-induced liver injury (DILI). Clinical, biochemical, histological spectrum and outcomes of AHM linked to severe DILI are not well studied. METHODS: Out of 1440 liver disease patients, 94 were found to have a severe liver injury and associated AHM intake. Thirty-three patients were suspected to have AHM-DILI on Roussel Uclaf Causality Assessment Scoring Method. Forty-seven and 30 of retrieved AHM samples were analyzed for heavy metals and hepatotoxic volatile organic compounds (hVOCs), respectively...
February 24, 2018: Indian Journal of Gastroenterology: Official Journal of the Indian Society of Gastroenterology
Sulakchanan Anandabaskaran, Vincent Ho
BACKGROUND: Bupropion is an antidepressant that is also used as a non-nicotine method to aid in smoking cessation. Bupropion-induced hepatotoxicity is quoted to affect between 0.1% and 1% of treated patients with either a hepatocellular and/or cholestatic pattern of damage. The mechanism of damage is considered to be predominantly immune-mediated with the presence of a hypersensitivity syndrome (fever, rash, eosinophilia, autoantibodies) and a short latency period (1-6 weeks). We believe our reporting of this case to the already existing small list of only seven cases in the world literature will help practicing physicians to deal with the diagnostic and management dilemmas that bupropion-induced hepatotoxicity brings...
February 24, 2018: Journal of Medical Case Reports
G J Webb, S R Rahman, C Levy, G M Hirschfield
BACKGROUND: The use of rifampicin for cholestatic pruritus is accompanied by concerns over safety, but the availability of real-world prescribing data is relatively limited. AIM: We sought to describe the rate and characteristics of rifampicin-induced hepatitis in a mixed aetiology cohort of patients with established liver disease and cholestatic pruritus. METHODS: Retrospective review of records for out-patients commenced on rifampicin for pruritus 2012-2016 inclusive...
February 22, 2018: Alimentary Pharmacology & Therapeutics
Jennifer Ryan, Ryan E Morgan, Yuan Chen, Laurie Volak, Robert T Dunn, Kenneth W Dunn
The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury (DILI) that often goes undetected during non-clinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow-up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models...
February 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Xiangying Yu, Man-Chu Chau, Wai Kit Tang, Chi-Kit Siu, Zhong-Ping Yao
Naproxen is one of the most consumed non-steroidal anti-inflammatory drugs and marketed as S-naproxen since R-naproxen is hepatotoxic. In this study, chiral recognition of naproxen has been investigated by tandem mass spectrometry (MS/MS). Among all diastereomeric complexes formed between naproxen and the examined chiral selectors, including cyclodextrins (α/β/γ-CD), modified phenylalanines (N-acetyl-phenylalanine, N-t-butoxycarbonyl-phenylalanine, N-9-fluorenylmethyloxycarbonyl-phenylalanine), amino acids (Trp, Phe, Tyr, His), glucose, tartaric acid and vancomycin, a novel binuclear metal bound diastereomeric complexes [(M(II))2 (S/R-Naproxen)(L-His)2 -3H]+ (M = Cu, Ni or Co with Cu being the best) could allow effective identification of the absolute configuration of naproxen and determination of its enantiomeric excess (ee) through MS/MS analysis...
February 17, 2018: Analytical Chemistry
Jun Cao, Yijun Mi, Cuilin Shi, Yicong Bian, Chenrong Huang, Zhijian Ye, Linsheng Liu, Liyan Miao
Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform...
February 15, 2018: Biochemical and Biophysical Research Communications
Cuiyuan Jin, Ting Luo, Zhengwei Fu, Yuanxiang Jin
Imazalil (IMZ), which is a widely used fungicide, can accumulate in the body and threaten an animal's health. However, this fungicide has adverse effects on aquatic organisms and ultimately affects human health when it leaches into the environment. Our research tried to determine that if IMZ might cause liver damage and its potential to cause-related diseases. In this study, male adult C57BL/6 mice were exposed to 0.1, 0.5, or 2.5 mg/kg body weight IMZ in drinking water for 15 weeks. Then, we evaluated the liver damage at the physiological, biochemical, and transcriptome levels in mice after chronic IMZ exposure...
February 16, 2018: Environmental Toxicology
Tapasree Basu, Sourav Panja, Anil Khushalrao Shendge, Abhishek Das, Nripendranath Mandal
Tannic acid (TA), a water soluble natural polyphenol with 8 gallic acids groups, is abundantly present in various medicinal plants. Previously TA has been investigated for its antimicrobial and antifungal properties. Being a large polyphenol, TA chelates more than 1 metal. Hence TA has been explored for potent antioxidant activities against reactive oxygen species (ROS), reactive nitrogen species (RNS) and as iron chelator in vitro thereby mitigating iron-overload induced hepatotoxicity in vivo. Iron dextran was injected intraperitoneally in Swiss albino mice to induce iron-overload triggered hepatotoxicity, followed by oral administration of TA for remediation...
February 15, 2018: Environmental Toxicology
Yuichi Yokoyama, Yoshifumi Sasaki, Natsuko Terasaki, Taku Kawataki, Koji Takekawa, Yumiko Iwase, Toshinobu Shimizu, Seigo Sanoh, Shigeru Ohta
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity...
February 14, 2018: Biological & Pharmaceutical Bulletin
Fatema R Saber, Ghada A Abdelbary, Maha M Salama, Dalia O Saleh, Magda M Fathy, Fathy M Soliman
Liver diseases are major health problem in Egypt influencing lifestyle and economy. The demand for nutraceutical hepatoprotective agents is crucial to ameliorate the side effects of synthetic drugs. The present study aims to evaluate antioxidant and hepatoprotective activities of extracts of Psidium guajava L. and Psidium cattleianum Sabine leaves and their nano-formulated liposomes against paracetamol-induced liver damage in rats. Secondary metabolites profile of P. guajava and P. cattleianum leaves was investigated using UPLC-PDA-ESI-qTOF-MSn...
March 2018: Food Research International
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