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Drug-induced hepatotoxicity

Jonathan G Stine, Jennifer Wang, Brian W Behm
Drug-induced liver injury is a rare but clinically important diagnosis. Vedolizumab is an α4β7 integrin inhibitor recently approved for use in patients with moderate-to-severe inflammatory bowel disease. Cases of hepatoxicity due to vedolizumab in the pre-marketing stage were rare, and all cases resolved upon drug withdrawal. We present here the first reported case of hepatotoxicity attributable to vedolizumab, which despite drug cessation persisted with chronic cholestatic liver injury.
September 28, 2016: Journal of Clinical and Translational Hepatology
Christopher Goldring, Daniel J Antoine, Frank Bonner, Jonathan Crozier, Chris Denning, Robert J Fontana, Neil A Hanley, David C Hay, Magnus Ingelman-Sundberg, Satu Juhila, Neil Kitteringham, Beatriz Silva-Lima, Alan Norris, Chris Pridgeon, James A Ross, Rowena Sison Young, Danilo Tagle, Belen Tornesi, Bob van de Water, Richard J Weaver, Fang Zhang, B Kevin Park
Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) means that no current single cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human DILI...
October 24, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Namrita Lall, Vivek Kumar, Debra Meyer, Nomasomi Gasa, Chris Hamilton, Motlalepula Matsabisa, Carel Oosthuizen
ETHNOPHARMACOLOGICAL RELEVANCE: The Natal gwarri or Natal ebony (Euclea natalensis A.DC.) is a deciduous tree found widespread throughout southern Africa, especially in Kwazulu-Natal and the southern cost. It has been widely used by indigenous communities such as the Zulus, Tsongas and Vendas for symptoms related to tuberculosis (TB). The decoctions made from the plant parts are administered for chest diseases to treat complications such as chest pains, bronchitis, pleurisy and asthma...
October 20, 2016: Journal of Ethnopharmacology
Madhusudanarao Vuda, Ashwin Kamath
Several commonly used medications impair mitochondrial function resulting in adverse effects or toxicities. Drug induced mitochondrial dysfunction may be a consequence of increased production of reactive oxygen species, altered mitochondrial permeability transition, impaired mitochondrial respiration, mitochondrial DNA damage or inhibition of beta-oxidation of fatty acids. The clinical manifestation depends on the specific drug and its effect on mitochondria. Given the ubiquitous presence of mitochondria and its central role in cellular metabolism, drug-mitochondrial interactions may manifest clinically as hepatotoxicity, enteropathy, myelosuppression, lipodystrophy syndrome or neuropsychiatric adverse effects, to name a few...
October 19, 2016: Mitochondrion
A D B Vliegenthart, R A Kimmitt, J H Seymour, N Z Homer, J I Clarke, M Eddleston, A Gray, D M Wood, P I Dargan, J G Cooper, D J Antoine, D J Webb, S C Lewis, D N Bateman, J W Dear
: Acetaminophen (paracetamol-APAP) is the commonest cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analysed from discovery (N=116) and validation (N=150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI...
October 22, 2016: Clinical Pharmacology and Therapeutics
Christoph Funk, Adrian Roth
Drug-induced liver injury (DILI) is a major concern for drug developers, regulators and clinicians. It is triggered by drug and xenobiotic insults leading to liver impairment or damage, in the worst-case liver failure. In contrast to acute "intrinsic" hepatotoxicity, DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and inconsistent temporal patterns and is therefore termed an idiosyncratic event. Involved are multifactorial, compound-dependent mechanisms and host-specific factors, making the prediction in preclinical test systems very challenging...
October 20, 2016: Archives of Toxicology
M Teresa Donato, Mireia López-Riera, José V Castell, María J Gómez-Lechón, Ramiro Jover
Disruption of the vectorial bile acid transport in the liver is a key feature of cholestatic drugs, although many causal and mechanistic aspects are still unknown. The aim of the present study was to explore if cholestatic drugs can repress or induce the expression of hepatic transporters. To this end, sandwich-cultured rat hepatocytes were treated with cholestatic and non-cholestatic (steatotic, non-hepatotoxic, etc.) drugs and the mRNA expression of 10 uptake and efflux biliary transporters was measured. Results evidenced that all cholestatic drugs cause extensive alterations in the mRNA expression of most biliary transporters...
October 17, 2016: Toxicology Letters
Fadia S Youssef, Mohamed L Ashour, Mansour Sobeh, Hesham A El-Beshbishy, Abdel Nasser Singab, Michael Wink
BACKGROUND: The Australian plant Eremophila maculata F. Muell (Scrophulariaceae) is cultivated worldwide as an ornamental plant. PURPOSE: This study was designed to assess the antioxidant and hepatoprotective activities of a methanol extract from E. maculata leaves (EMM) both in vitro and in vivo (rats) experiments. Detailed phytochemical study was done on the extract followed by molecular docking experiments on TNF-α ascertain the efficacy of the isolated compounds...
November 15, 2016: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Medine Cumhur Cüre, Erkan Cüre, Yıldıray Kalkan, Aynur Kırbaş, Levent Tümkaya, Arif Yılmaz, Ayşegül Küçükali Türkyılmaz, İbrahim Şehitoğlu, Süleyman Yüce
BACKGROUND: Cisplatin (Cis) is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α). Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. AIMS: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis...
September 2016: Balkan Medical Journal
Delilah F G Hendriks, Lisa Fredriksson Puigvert, Simon Messner, Wolfgang Mortiz, Magnus Ingelman-Sundberg
Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound's potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days...
October 19, 2016: Scientific Reports
Jae-Woo Jang, Yeonhwa Song, Kang Mo Kim, Jin-Sun Kim, Eun Kyung Choi, Joon Kim, Haengran Seo
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers worldwide and is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in HCC patients. METHODS: Here, we developed a fluorescence image-based phenotypic screening system in vitro to identify HCC-specific drugs in co-cultures of HCC cells with hepatocytes. To this end, we identified two distinctive markers of HCC, CHALV1 and AFP, which are highly expressed in HCC cell lines and liver cancer patient-derived materials...
October 18, 2016: BMC Cancer
Frank F Vincenzi, Philippe Lunetta
While SCUBA diving, a 44-year-old Caucasian patient had an abnormal cardiac rhythm, presumably Torsade de Pointes (TdP), during the initial descent to depth. Upon surfacing, she developed ventricular fibrillation and died. The patient had been treated for mild depression for nearly a year with citalopram 60 mg per day, a drug known to cause prolonged QT interval. She had also been treated with two potentially hepatotoxic drugs. Liver impairment causes selective loss of cytochrome P450 (CYP) 2C19 activity, the major pathway for metabolism of citalopram...
December 2015: Drug Saf Case Rep
Kuo Du, Anup Ramachandran, Hartmut Jaeschke
Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death...
October 4, 2016: Redox Biology
Francia C Díaz, Esteban Sáez-González, Salvador Benlloch, Diego Álvarez-Sotomayor, Isabel Conde, Begoña Polo, María García, María Rodríguez, Martín Prieto
:  Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support. MATERIAL AND METHODS: We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-)...
November 2016: Annals of Hepatology
Kana Yanagihara, Yujung Liu, Kei Kanie, Kazuo Takayama, Minako Okamura, Mitsuhi Hirata, Takayuki Fukuda, Mika Suga, Hiroki Nikawa, Hiroyuki Mizuguchi, Ryuji Kato, Miho K Furue
Functional hepatocytes derived from human pluripotent stem cells (hPSCs) have potential as tools for predicting drug-induced hepatotoxicity in the early phases of drug development. However, the propensity of hPSC lines to differentiate into specific lineages is reported to differ. The ability to predict low propensity of hPSCs to differentiate into hepatocytes would facilitate the selection of useful hPSC clones and substantially accelerate development of hPSC-derived hepatocytes for pharmaceutical research...
October 12, 2016: Stem Cells and Development
Pravin Rathi, Pravir Gambhire
Abdomen is involved in 11% of patients with extra-pulmonary tuberculosis; The most common site of involvement is the ileocaecal region, other locations of involvement, in order of descending frequency, are the ascending colon, jejunum, appendix, duodenum, stomach, oesophagus, sigmoid colon, and rectum. Apart from the basic work up, Investigations like CT scan, EUS, Capsule endoscopy, Balloon enteroscopy, Ascitic fluid ADA, TB-PCR, GeneXpert, Laproscopy are being increasingly used to diagnose tuberculosis.Therapy with standard antituberculous drugs is usually highly effective for intestinal TB...
February 2016: Journal of the Association of Physicians of India
Ryo Mitsugi, Kyohei Sumida, Yoshiko Fujie, Robert H Tukey, Tomoo Itoh, Ryoichi Fujiwara
Trovafloxacin is an antibiotic that was withdrawn from the market relatively soon after its release due to the risk of hepatotoxicity. Trovafloxacin is mainly metabolized to its acyl-glucuronide by uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1. In this study, we examined whether the acyl-glucuronide is involved in the development of hepatotoxicity. A UGT1A1-induced cell model was developed and the toxicity of trovafloxacin acyl-glucuronide was evaluated. The UGT1A1-induced cell model was developed by treating HepG2 cells with chrysin for 48 h...
2016: Biological & Pharmaceutical Bulletin
S Wattanapokayakit, T Mushiroda, H Yanai, N Wichukchinda, C Chuchottawon, S Nedsuwan, A Rojanawiwat, S Denjanta, T Kantima, J Wongyai, W Suwankesawong, W Rungapiromnan, R Kidkeukarun, W Bamrungram, A Chaiwong, S Suvichapanich, S Mahasirimongkol, K Tokunaga
BACKGROUND: Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI. OBJECTIVE: To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients. METHODS: We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls...
October 2016: International Journal of Tuberculosis and Lung Disease
Yan Jiang, Feng-Jie Liu, Yu-Mei Wang, Hui-Jun Li
Although natural products (NPs) from ethnomedical plants have played a vital role in modern drug discovery, separation and purification of bioactive compounds from plant extract is still challenging. In this study, a dereplication strategy using HPLC-QTOF-MS was employed to rapidly discover and highly targeted isolate the novel hepatoprotective triterpenoid saponins from the methanol extract of Celosiae Semen. Firstly, four known saponins, i.e. celosin H, celosin I, celosin J, and pseudoginsenoside RT1 were selected as model compounds, and their fragmentation patterns in ESI-QTOF-MS/MS were characterized...
October 3, 2016: Journal of Pharmaceutical and Biomedical Analysis
Katalin Jemnitz, Attila Bátai-Konczos, Mónika Szabó, Enikő Ioja, Orsolya Kolacsek, Tamás I Orbán, György Török, László Homolya, Eszter Kovács, István Jablonkai, Zsuzsa Veres
Increasing number of papers demonstrate that Kupffer cells (KCs) play a role in the development of drug induced liver injury (DILI). Furthermore, elevated intracellular Ca(2+) level of hepatocytes is considered as a common marker of DILI. Here we applied an in vitro model based on hepatocyte mono- and hepatocyte/KC co-cultures (H/KC) isolated from transgenic rats stably expressing the GCaMP2 fluorescent Ca(2+) sensor protein to investigate the effects of polycationic (G5), polyanionic (G4.5) and polyethylene-glycol coated neutral (G5 Peg) dendrimers known to accumulate in the liver, primarily in KCs...
October 4, 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
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