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

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.

Download Full-text

Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

International Journal of Molecular Sciences ◽

10.3390/ijms22062954 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2954

Author(s):

Alison Jee ◽

Samantha Christine Sernoskie ◽

Jack Uetrecht

Keyword(s):

Immune Response ◽

Immune System ◽

T Cell ◽

Liver Injury ◽

Clinical Manifestations ◽

Adaptive Immune System ◽

Human Leukocyte ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.

Download Full-text

Characterisation of the Immune Response in Patients with Drug Induced Liver Injury

10.26226/morressier.58eb975cd462b80290b4fa62 ◽

2017 ◽

Author(s):

Giacomo Germani

Keyword(s):

Immune Response ◽

Liver Injury ◽

Drug Induced ◽

Drug Induced Liver Injury

Download Full-text

Mitochondrial Dynamics in Drug-Induced Liver Injury

Livers ◽

10.3390/livers1030010 ◽

2021 ◽

Vol 1 (3) ◽

pp. 102-115

Author(s):

Anup Ramachandran ◽

David S. Umbaugh ◽

Hartmut Jaeschke

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Membrane Lipids ◽

Mitochondrial Dynamics ◽

Adaptive Responses ◽

Drug Induced ◽

Biologically Relevant ◽

Drug Induced Liver Injury ◽

Relevant Role ◽

Atp Generation

Mitochondria have been studied for decades from the standpoint of metabolism and ATP generation. However, in recent years mitochondrial dynamics and its influence on bioenergetics and cellular homeostasis is also being appreciated. Mitochondria undergo regular cycles of fusion and fission regulated by various cues including cellular energy requirements and pathophysiological stimuli, and the network of critical proteins and membrane lipids involved in mitochondrial dynamics is being revealed. Hepatocytes are highly metabolic cells which have abundant mitochondria suggesting a biologically relevant role for mitochondrial dynamics in hepatocyte injury and recovery. Here we review information on molecular mediators of mitochondrial dynamics and their alteration in drug-induced liver injury. Based on current information, it is evident that changes in mitochondrial fusion and fission are hallmarks of liver pathophysiology ranging from acetaminophen-induced or cholestatic liver injury to chronic liver diseases. These alterations in mitochondrial dynamics influence multiple related mitochondrial responses such as mitophagy and mitochondrial biogenesis, which are important adaptive responses facilitating liver recovery in several contexts, including drug-induced liver injury. The current focus on characterization of molecular mechanisms of mitochondrial dynamics is of immense relevance to liver pathophysiology and have the potential to provide significant insight into mechanisms of liver recovery and regeneration after injury.

Download Full-text

Metabolic activation in drug-induced liver injury

Drug Metabolism Reviews ◽

10.3109/03602532.2011.605791 ◽

2012 ◽

Vol 44 (1) ◽

pp. 18-33 ◽

Cited By ~ 60

Author(s):

Louis Leung ◽

Amit S. Kalgutkar ◽

R. Scott Obach

Keyword(s):

Liver Injury ◽

Metabolic Activation ◽

Drug Induced ◽

Drug Induced Liver Injury

Download Full-text

Isoniazid and Rifampicin Produce Hepatic Fibrosis through an Oxidative Stress-Dependent Mechanism

International Journal of Hepatology ◽

10.1155/2020/6987295 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Ayan Biswas ◽

Suman Santra ◽

Debasree Bishnu ◽

Gopal Krishna Dhali ◽

Abhijit Chowdhury ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Hepatic Fibrosis ◽

Stellate Cell ◽

Progressive Increase ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Stress Dependent ◽

Liver Collagen

Background & Aims. Chronic hepatitis (CH) has emerged as a distinct outcome of drug-induced liver injury (DILI). Combination therapy of Isoniazid (INH) and Rifampicin (RMP) which is widely used for prolonged periods can cause acute hepatotoxicity and has been also incriminated in chronic DILI. We sought evidence of the production of hepatic fibrosis on long-term INH-RMP treatment through experiments in BALB/c mice exposed to INH-RMP. Methods. A combined dose of INH (50 mg) and RMP (100 mg) per kg body weight per day was administered to mice by oral gavage, 6 days a week, for 4 to 24 weeks for the assessment of liver injury, oxidative stress, and development of hepatic fibrosis, including demonstration of changes in key fibrogenesis linked pathways and mediators. Results. Progressive increase in markers of hepatic stellate cell (HSC) activation associated with changes in matrix turnover was observed between 12 and 24 weeks of INH-RMP treatment along with the elevation of liver collagen content and significant periportal fibrosis. These were associated with concurrent apoptosis of the hepatocytes, increase in hepatic cytochrome P450 2E1 (CYP2E1), NADPH oxidase (NOX) activity, and development of hepatic oxidative stress. Conclusions. INH-RMP can activate HSC through generation of NOX-mediated oxidative stress, leading to the development of liver fibrosis.

Download Full-text