Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Fu, Siyu; Wu, Dongbo; Jiang, Wei; Li, Juan; Jiang, Long; Jia, Chengyao; Zhou, Tong

doi:10.3389/fphar.2019.01667

Cited by 87 publications

(76 citation statements)

References 133 publications

(236 reference statements)

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“…The latter can be classified as hepatitis (mostly due to hepatocyte necrosis), cholestatic (i.e., bile duct damage or cholangiolitis) or mixed injury ( Stefan and Hamilton, 2010 ). Despite the variety of its clinical presentations, DILI still does not display specific biomarkers, leading to abnormal liver tests and often the dysfunction is only identified by exclusion of other etiologies, which can lead to life-threatening clinical situations ( Devarbhavi, 2012 ; Fu et al, 2020 ). Indeed, the identification of new molecular biomarkers has been investigated in order to improve diagnosis and treatment of DILI.…”

Section: Drug-induced Hepatotoxicity: Overview Liver Metabolism and mentioning

confidence: 99%

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A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

Serras

Rodrigues

Cipriano

et al. 2021

Front. Cell Dev. Biol.

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The poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields.

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Section: Drug-induced Hepatotoxicity: Overview Liver Metabolism and mentioning

confidence: 99%

“…Indeed, the identification of new molecular biomarkers has been investigated in order to improve diagnosis and treatment of DILI. However, its applicability is still limited ( Fu et al, 2020 ). Thus, DILI is largely unrecognized and underreported, such that the true incidence is unknown.…”

Section: Drug-induced Hepatotoxicity: Overview Liver Metabolism and mentioning

confidence: 99%

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

Serras

Rodrigues

Cipriano

et al. 2021

Front. Cell Dev. Biol.

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show abstract

“…Currently, serological biomarkers used in DILI diagnosis include ALT, aspartate aminotransferase (AST), ALP, and TBL [ 264 ].…”

Section: Biomarkersmentioning

confidence: 99%

“…Due to the liver-specificity of GLDH, measuring its levels can differentiate liver from muscle injury, being a useful marker when ALT is elevated [ 267 ]. Although helpful, its sensitivity as diagnostic biomarker is poor, since there is controversy about its accuracy in predicting hepatocyte necrosis [ 167 , 264 ].…”

Section: Biomarkersmentioning

confidence: 99%

Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

et al. 2021

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Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.

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“…The secreted miRNAs maintain stability in body fluids and can be isolated for examination for related diseases. MiRNAs also display diagnostic tools for degenerative diseases such as neurodegenerative disorders and liver failure and are receiving attention as important biomarkers [ 21 , 22 ]. As several degenerative diseases including Alzheimer’s disease (AD), circulating miRNA levels increase which is considered as potential non-invasive biomarkers for diagnosis and prognosis.…”

Section: Introductionmentioning

confidence: 99%

Research Trends in the Efficacy of Stem Cell Therapy for Hepatic Diseases Based on MicroRNA Profiling

Kweon

Kim

Jun

et al. 2020

IJMS

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Liver diseases, despite the organ’s high regenerative capacity, are caused by several environmental factors and persistent injuries. Their optimal treatment is a liver transplantation. However, this option is limited by donor shortages and immune response issues. Therefore, many researchers have been interested in identifying the therapeutic potential in treating irreversible liver damage based on stem cells and developing suitable therapeutic agents. Mesenchymal stem cells (MSCs), which are representative multipotent stem cells, are known to be highly potential stem cell therapy compared to other stem cells in the clinical trial worldwide. MSCs have therapeutic potentials for several hepatic diseases such as anti-fibrosis, proliferation of hepatocytes injured, anti-inflammation, autophagic mechanism, and inactivation of hepatic stellate cells. There are much data regarding clinical treatments, however, the data for examining the efficacy of stem cell treatment and the correlation between the stem cell engraftment and the efficacy in liver diseases is limited due to the lack of monitoring system for treatment effectiveness. Therefore, this paper introduces the characteristics of microRNAs (miRNAs) and liver disease-specific miRNA profiles, and the possibility of a biomarker that miRNA can monitor stem cell treatment efficacy by comparing miRNAs changed in liver diseases following stem cell treatment. Additionally, we also discuss the miRNA profiling in liver diseases when treated with stem cell therapy and suggest the candidate miRNAs that can be used as a biomarker that can monitor treatment efficacy in liver diseases based on MSCs therapy.

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Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

Cited by 87 publications

References 133 publications

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

Research Trends in the Efficacy of Stem Cell Therapy for Hepatic Diseases Based on MicroRNA Profiling

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