Drug-Induced Hepatotoxicity Publications (6509)


Drug-Induced Hepatotoxicity Publications

Biomark Med
Biomark Med 2017 Jan 18. Epub 2017 Jan 18.
Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
J Integr Med
J Integr Med 2017 Jan;15(1):27-36
School of Biosciences and Technology, VIT University, Vellore-632014, Tamilnadu, India.

Drug-induced liver injury is the common adverse effect seen in patients receiving antituberculosis drugs (ATDs). There are several risk factors associated with the development of hepatotoxicity in such patients. Though there have been appreciable efforts taken by carrying out studies investigating the efficacy of several natural and synthetic compounds in minimising this effect, the only choice available for clinicians is withdrawal of drugs. Read More

This review would give a precise idea of ATD-induced hepatotoxicity, its underlying mechanisms and alternative therapies for the same.

1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. Read More

The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane. CCl4 treatment increased blood AST/ALT levels, liver caspase-3 and -9 activities and liver malondialdehyde, accompanied by centrilobular hepatocyte necrosis. Halothane increased AST/ALT levels, caspase-3 and -8 activities (but not malondialdehyde) concomitant with widespread hepatotoxicity. In vitro, CCl4 treatment increased caspase-9 activity and decreased both mitochondrial membrane potential (MMP) and cell viability. In co-culture, halothane increased caspase-8 activity and decreased MMP and cellular viability. There were no toxic responses in CYP2E1 knockdown in monoculture and co-culture. 3. CYP2E1-inducing compounds play a pivotal role in halogenated hydrocarbon toxicity. 4. Changes in hepatocyte caspase-8 and -9 activities could be novel biomarkers of metabolites causing DILI, and in pre-clinical development of new pharmaceuticals can predict nascent DILI in the clinical stage.

Biomed Res Int
Biomed Res Int 2016 18;2016:7150391. Epub 2016 Dec 18.
China Military Institute of Chinese Medicine, Integrative Medical Center, 302 Military Hospital of China, Beijing 10003, China.

In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI), has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM), including global overview on herbal-induced liver injury (HILI), current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. Read More

As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury.

Biomed Res Int
Biomed Res Int 2016 15;2016:4780872. Epub 2016 Dec 15.
Pacific University School of Pharmacy, 222 SE 8th Avenue No. 451, Hillsboro, OR 97123, USA.

Species-specific differences in the hepatotoxicity of acetaminophen (APAP) have been shown. To establish a monkey model of APAP-induced hepatotoxicity, which has not been previously reported, APAP at doses up to 2,000 mg/kg was administered orally to fasting male and female cynomolgus monkeys (n = 3-5/group) pretreated intravenously with or without 300 mg/kg of the glutathione biosynthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). In all the animals, APAP at 2,000 mg/kg with BSO but not without BSO induced hepatotoxicity, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Read More

Plasma levels of APAP and its reactive metabolite N-acethyl-p-benzoquinone imine (NAPQI) increased 4 to 7 hr after the APAP treatment. The mean Cmax level of APAP at 2,000 mg/kg with BSO was approximately 200 µg/mL, which was comparable to high-risk cutoff value of the Rumack-Matthew nomogram. Interestingly, plasma alanine aminotransferase (ALT) did not change until 7 hr and increased 24 hr or later after the APAP treatment, indicating that this phenotypic outcome was similar to that in humans. In addition, circulating liver-specific miR-122 and miR-192 levels also increased 24 hr or later compared with ALT, suggesting that circulating miR-122 and miR-192 may serve as potential biomarkers to detect hepatotoxicity in cynomolgus monkeys. These results suggest that the hepatotoxicity induced by APAP in the monkey model shown here was translatable to humans in terms of toxicokinetics and its toxic nature, and this model would be useful to investigate mechanisms of drug-induced liver injury and also potential translational biomarkers in humans.

Toxicol. Sci.
Toxicol Sci 2017 Jan 9. Epub 2017 Jan 9.
Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, 138673, Singapore

Organ toxicity, particularly liver toxicity, remains one of the major reasons for termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would therefore find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults. Read More

Transcriptome microarray analysis was performed on whole larvae or dissected adult livers. Integration of data sets from different drug treatments at different stages identified common upregulated detoxification pathways. Within these were candidate biomarkers which recurred in multiple treatments. We prioritized four highly upregulated genes encoding enzymes acting in distinct phases of the drug metabolism pathway. Through promoter isolation and fosmid recombineering, eGFP reporter transgenic zebrafish lines were generated and evaluated for their response to DILI drugs. Three of the four generated reporter lines showed a dose and time dependent induction in endodermal organs to reference drugs and an expanded drug set. In conclusion, through integrated transcriptomics and transgenic approaches, we have developed parallel independent zebrafish in vivo screening platforms able to predict organ toxicities of preclinical drugs.

Indian J Gastroenterol
Indian J Gastroenterol 2017 Jan 9. Epub 2017 Jan 9.
Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.

Antitubercular therapy (ATT)-induced hepatotoxicity is often over looked and active tuberculosis is considered a contraindication for liver transplantation, however it might be the only lifesaving option to certain patients of acute liver failure (ALF) due to ATT. We have assessed the outcome of live donor liver transplantation in ATT-induced ALF. A retrospective analysis of all the cases of ALF that underwent liver transplantation from 2006 to 2014 at the Amrita Institute of Medical Sciences was done. Read More

A total of seven (7.7%) patients with ATT-induced ALF who had underwent live donor liver transplantation were included in the study. Out of seven patients, three (42.8%) had established diagnosis of tuberculosis and the remaining (58.2%) patients were started on ATT empirically. The median duration of ATT intake was 2 months. All the patients underwent live donor liver transplant as they met King's College criteria, and their model for end-stage liver disease score was above 35 on admission, receiving graft from first degree relatives. Histopathology of explant liver showed pan acinar necrosis. Restarting of ATT after transplant was individualized. It was restarted only in two (28%) patients with prior sputum-positive pulmonary tuberculosis after a median time of 27 days after transplant. ATT was not restarted in rest of the (72%) patients. Postoperative mortality was seen in two (28%) patients due to conditions that masquerade the ATT-induced acute liver failure. The overall survival rate was 71.4% with a median follow up of 22 months. Live donor-related transplantation is feasible option in ATT-induced acute liver failure. Restarting of ATT post liver transplant is feasible and should be individualized along with frequent monitoring of immunosuppressant levels; however, if the primary diagnosis of tuberculosis was empirical, reintroduction of ATT can be omitted.

Toxicology 2017 Jan 4;378:65-75. Epub 2017 Jan 4.
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China. Electronic address: