Hepatotoxicity Research Articles

High-Throughput Assessment of Bile Salt Export Pump Inhibition Using RapidFire-MS and DESI-MS.

The bile salt export pump (BSEP) assay is widely used to evaluate the potential for drug-induced liver injury (DILI) early in the drug discovery process. While traditional liquid chromatography-mass spectrometry (LC-MS)-based approaches have been utilized for BSEP activity testing, they have intrinsic limitations in either throughput or the requirement for sample preparation and are difficult to scale up in order to screen drug candidates. Here we demonstrate the use of two different high-throughput MS methods based on solid-phase extraction (SPE) and desorption electrospray ionization (DESI) for high-throughput BSEP activity assessment in a label-free manner, with minimal needs for sample workup, at sampling rates of ∼11 and ∼5.5 s/sample, respectively. Both approaches were validated, compared, and successfully applied to the evaluation of 96 drug candidates for the inhibition of taurocholic acid (TCA) transport using BSEP vesicles.

Drug-induced liver injury associated with savolitinib: a novel case report and causality assessment

BackgroundSavolitinib, a small molecule inhibitor, has gained approval as the inaugural medication in China that specifically targets MET kinase. Patients with advanced non-small cell lung cancer (NSCLC) who show MET exon 14 skipping now have a new and innovative treatment option available.Case reportIn this case report, we describe a patient who experienced drug-induced liver injury (DILI) due to the administration of savolitinib. After being prescribed with savolitinib (400 mg per day, oral), a 73-year-old male diagnosed with stage IV NSCLC with MET exon 14 skipping mutation experienced an increase in liver enzymes and bilirubin levels according to his laboratory tests conducted one month later. Following a 14-day course of hepatoprotective medication, the liver function reverted back to its normal state. After receiving savolitinib (200 mg per day, oral) for one week, the patient was once again diagnosed with severe liver impairment. Then savolitinib was discontinued and received treatment with hepatoprotective drugs for one week. Following the restoration of normal liver function, another attempt was made to administer a small amount of savolitinib (100 mg per day, oral). Thus far, the patient has been followed up and there has been no recurrence of liver damage. Additionally, the lung CT scan revealed ongoing tumor shrinkage with no apparent indications of spreading or metastasis. The Roussel Uclaf Causality Assessment Method (RUCAM) determined that savolitinib was “highly probable” cause of DILI. Moderate-severe was determined to be the extent of DILI severity.ConclusionTo the best of our understanding, this is the initial instance of DILI resulting from the use of savolitinib as a standalone treatment in a real-world setting. During the administration of savolitinib, healthcare professionals should carefully consider the potential occurrence of DILI. Administering the patient with a small amount of savolitinib resulted in a remarkable response against the tumor, leading us to speculate that the effectiveness of savolitinib might be associated with its plasma concentration. Studying the pharmacokinetics and pharmacodynamics (PK/PD) of savolitinib is beneficial for tailoring and accurately prescribing the medication to each individual.

Norethisterone induced drug induced autoimmune hepatitis: a case report

Norethisterone induced drug induced autoimmune hepatitis: a case report

Clinical spectrum of drug induced liver injury in tertiary care hospital

Clinical spectrum of drug induced liver injury in tertiary care hospital

Clinical profile of drug induced liver injury presenting as acute liver injury to a tertiary care center in South India

Clinical profile of drug induced liver injury presenting as acute liver injury to a tertiary care center in South India

Cholesterol Allosterically Modulates the Structure and Dynamics of the Taurocholate Export Pump (ABCB11).

The BSEP/ABCB11 transmembrane protein translocates taurine- and glycine-conjugated bile salts across the hepatocyte bilayer driven by ATP-hydrolysis. Direct inhibition of BSEP/ABCB11 leads to idiosyncratic drug-induced liver injury. ABCB11 is localized within the cholesterol-enriched lipid raft, and membrane cholesterol depletion leads to impaired taurocholate transport. However, structural insight into the mechanism of the cholesterol-mediated regulation of ABCB11 activity remains elusive. We used extensive molecular dynamics simulation coupled with well-tempered metadynamics to elucidate the role of membrane cholesterol in the structure and dynamics of ABCB11. We identified specific high-residence binding sites for cholesterol within the transmembrane domain. The free-energy simulations have elucidated that the bound cholesterol stabilizes the "inward-open" conformation of the protein. Cholesterol-ABCB11 interactions trigger allosteric communications between the transmembrane and nucleotide-binding domains through the linker region. Cholesterol depletion destabilizes the allosteric network of the protein. As a result, it adopts a more collapsed form with a reduced volume of the taurocholate-binding pocket.

Drug-induced cholestatic liver diseases.

Cholestatic DILI is an important and frequently challenging differential diagnosis in patients presenting with elevated liver tests with predominant elevation in alkaline phosphatase. A number of competing etiologies need to be ruled out, such as hepatobiliary malignancy, choledocholithiasis, cholestatic forms of viral hepatitis, cholestasis of sepsis, primary and secondary cholangitis, and right-sided cardiac failure to name a few. Important advances have occurred in the understanding and knowledge of the clinical phenotypes, new etiological agents, risk factors, pathophysiology, and genetic determinants of drug-induced cholestasis since the last review on drug-induced cholestasis was published in Hepatology in 2011. Secondary sclerosing cholangitis (SSC) due to drugs has been well documented for several different drugs. Checkpoint inhibitors are one of the types of drugs shown to lead to secondary sclerosing cholangitis. Several new herbal and dietary supplements have recently been shown to lead to cholestatic liver injury. A number of genetic risk factors for cholestasis due to drugs have been identified in the last decade, and the pathogenesis behind cholestatic injury is better defined. In this review, the focus is on diagnostic approach and description of new clinical phenotypes such as secondary sclerosing cholangitis and vanishing bile duct syndrome. Furthermore, the review provides an overview of the risk factors, genetic determinants, and the pathophysiology of hepatobiliary transporters leading to cholestasis. Management, areas of uncertainty, and future direction are also presented.

The Feasibility of using Liver Function Indices and FibroScan in combination to predict the occurrence of anti-tuberculosis drug-induced liver injury in patients with liver disease

Background: The study aims to assess the feasibility of using a combined approach of liver function indices and FibroScan measurements as a predictive tool for the early detection of anti-tuberculosis drug-induced liver injury (DILI) in patients with existing liver disease. Methods: A retrospective cohort study was conducted, including adult tuberculosis patients with documented liver disease. Liver function was assessed using standard biochemical parameters, and FibroScan examinations were performed to determine liver stiffness measurement (LSM). Patients were monitored for clinical and biochemical signs of DILI throughout treatment. Logistic regression models and Receiver Operating Characteristic (ROC) curves were used for data analysis. Statistical significance was set at p < 0.05. Results: Patients who developed DILI showed significantly higher levels of ALT, AST, total bilirubin, GGT, and LSM, with strong positive correlations between these markers and DILI occurrence. Logistic regression analysis revealed elevated ALT, AST, TBIL, and GGT were strongly associated with an increased likelihood of DILI. The area under the ROC curves indicated excellent predictive accuracy of these parameters. A nomogram for predicting DILI based on the combined biomarkers was established. Conclusion: The study demonstrates the feasibility of utilizing liver function indices and FibroScan measurements in combination to predict anti-tuberculosis DILI. The results highlight the importance of baseline liver health assessment and offer promising implications for clinical practice, aiding in individualized risk estimation and therapeutic decision-making for patients with liver disease initiating anti-tuberculosis therapy. Further validation in larger cohorts is warranted to strengthen the predictive model.

Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models

Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.

Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy

ABSTRACT Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs. Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic – pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2.

Hepatotoxicity during anti tuberculosis chemotherapy

Introduction: Despite their efficacy in tuberculosis treatment, side-effects of anti-tuberculosis drugs can be serious or fatal. The aim of our study is to determine the prevalence of hepatic toxicities associated with anti-tuberculosis drugs, their evolutionary aspects, and their management. Patients and methods: A retrospective descriptive study including 82 patients having received antituberculosis treatment and who pre-sented a hepatic cytolysis, collected at the Tuberculosis and Respiratory Diseases Control Department of Batna- Algeria between 2016 -2023. The aim of our study is to determine the prevalence of hepatic toxicities of anti-tuberculosis drugs, their evolutionary aspects, as well as the modalities of their management. Results: 82 out of 119 (69.23%) patients who experienced other adverse events were recruited between 2016 and 2023, aged between 15 and 86 years, with an average age of 43 years and a female predominance of 63.41%. Cholestasis syndrome was noted in 21 patients and frank jaundice in 4. Cytolysis was discovered incidentally in 68% of patients; it was mild in 56 (68.29%), moderate in 16 (19.51%) and severe in 10 (12.19%). Transaminase disturbance appeared within 3 months in 76.82% of cases, whereas a delay of 30 days was noted for normalisation of the liver function test after cessation of anti-tuberculosis treatment in 62 (76%) patients. Definitive discontin-uation of isoniazid (INH) was adopted in 17 (20%) patients, while a reduction in the doses of rifampicin and isoniazid was decided in 65 (80%) patients. Conclusion: Drug-induced hepatitis is one of the major side-effects of anti-tuberculosis drugs and can be lethal, hence the need for rapid and appropriate management. Healthcare professionals need to be informed about the types of suspected adverse drug reactions, they should report in subjects at risk.

Prediction of Drug-Induced Liver Injury: From Molecular Physicochemical Properties and Scaffold Architectures to Machine Learning Approaches.

The process of developing new drugs is widely acknowledged as being time-intensive and requiring substantial financial investment. Despite ongoing efforts to reduce time and expenses in drug development, ensuring medication safety remains an urgent problem. One of the major problems involved in drug development is hepatotoxicity, specifically known as drug-induced liver injury (DILI). The popularity of new drugs often poses a significant barrier during development and frequently leads to their recall after launch. In silico methods have many advantages compared with traditional invivo and invitro assays. To establish a more precise and reliable prediction model, it is necessary to utilize an extensive and high-quality database consisting of information on drug molecule properties and structural patterns. In addition, we should also carefully select appropriate molecular descriptors that can be used to accurately depict compound characteristics. The aim of this study was to conduct a comprehensive investigation into the prediction of DILI. First, we conducted a comparative analysis of the physicochemical properties of extensively well-prepared DILI-positive and DILI-negative compounds. Then, we used classic substructure dissection methods to identify structural pattern differences between these two different types of chemical molecules. These findings indicate that it is not feasible to establish property or substructure-based rules for distinguishing between DILI-positive and DILI-negative compounds. Finally, we developed quantitative classification models for predicting DILI using the naïve Bayes classifier (NBC) and recursive partitioning (RP) machine learning techniques. The optimal DILI prediction model was obtained using NBC, which combines 21 physicochemical properties, the VolSurf descriptors and the LCFP_10 fingerprint set. This model achieved a global accuracy (GA) of 0.855 and an area under the curve (AUC) of 0.704 for the training set, while the corresponding values were 0.619 and 0.674 for the test set, respectively. Moreover, indicative substructural fragments favorable or unfavorable for DILI were identified from the best naïve Bayesian classification model. These findings may help prioritize lead compounds in the early stage of drug development pipelines.

Chinese expert consensus on diagnosis and treatment of antirheumatic drug-induced liver injury(2024)

Rheumatic diseases are a common group of chronic diseases that typically require long-term medication to control. Antirheumatic drugs may cause liver damage which requires prompt detection treatment to avoid irreversible damage. Liver damage induced by medication for rheumatoid arthritis has unique clinical manifestations and is difficult to distinguish from liver diseases related to the primary illness, often requiring the involvement of hepatologists to discuss and determine the treatment plan. To improve the understanding and management of anti rheumatic drug-induced liver injury among clinicians, especially rheumatologists, the Rheumatology Branch of the Chinese Medical Association and other experts in related fields formed this consensus after multiple discussions and revisions based on relevant research progress in recent years. Based on the Chinese Guidelines for diagnosis and management of drug-induced liver injury (2023), this consensus highlights the characteristics of rheumatic diseases and rheumatology medications, clarifies the anti rheumatic drugs that can cause liver injury, the liver injury caused by rheumatic diseases, the susceptible groups of anti rheumatic drug-induced injury, the diagnostic process of anti rheumatic drug-induced liver injury, and the indications for rheumatology physicians' consultation in the case of anti rheumatic drug-induced liver injury. It is hoped that the content of this consensus will be useful for practicing rheumatologists and that it can provide guidance for rheumatologists in the scientific management of anti rheumatic drug-induced liver injury.

Useful biomarkers for predicting poor prognosis of patients with drug-induced liver injury: A retrospective cohort study

BackgroundDrug-induced liver injury (DILI) plays an important role in liver failure and causes mortality. Patients with DILI compatible with Hy's law are associated with poorer outcomes. However, the predictive accuracy of Hy's law is not good enough in clinical practice. This study aimed to investigate the optimal values of biomarkers associated with the prognosis of DILI. MethodsFrom June 1, 2014-May 30, 2022, patients with reported DILI were included. Patients' characteristics, drugs, DILI type, liver enzymes, and comorbidities were assessed. The associations with DILI-related comorbidities and survival were analyzed. ResultsNinety-five DILI patients were enrolled, 5 patients died of liver failure, and 23 patients died within 56 weeks after DILI. This study found that 15 mg/dL of total bilirubin, 1000 U/L of ALT, and 2 of PT-INR were optimal cut-off values in predicting DILI-related mortality. For the overall survival, patients with sepsis (HR:5.053, 95% CI:1.594–16.018, p = 0.006), malignancy (HR:4.371, 95% CI:1.573–12.147, p = 0.005), or end-stage renal disease (HR:7.409, 95% CI:1.404–39.103, p = 0.018) were independent poor prognostic factors in multivariate Cox regression analysis. ConclusionsTotal bilirubin >15 mg/dL, ALT >1000 U/L, and PT-INR >2 are useful biomarkers in predicting DILI-related mortality. DILI patients with sepsis, malignancy, or end-stage renal disease are associated with worse overall survival.

Necrotic Liver Lesion Resolution: Another Mode of Liver Regeneration.

The liver has the great ability to regenerate after partial resection or injury, and the mechanisms underlying liver regeneration have been extensively investigated. Interestingly, acute liver injuries triggered by various etiologies are associated with the formation of necrotic lesions, and such necrotic lesions are also rapidly resolved. However, how necrotic liver lesions are repaired has not been carefully investigated until recently. In this review, we briefly summarize the spatiotemporal process of necrotic liver lesion resolution in several liver injury models including immune-mediated liver injury and drug-induced liver injury. The roles of liver nonparenchymal cells and infiltrating immune cells in controlling necrotic liver lesion resolution are discussed, which may help identify potential therapies for acute liver injury and failure.

Therapeutic Potential of Flavonoids in Modulating Mitochondrial Activity in Liver Cancer: Insights from HepG2 Cell Studies

Background: Cancer, a leading cause of mortality globally, affects various organs, including the liver, with liver cancer contributing to approximately 830,000 deaths in 2020. In Malaysia, liver cancer is increasingly prevalent. The HepG2 cell line, derived from human hepatoma, is widely used for studying liver cancer and drug-induced liver injuries. Flavonoids, a group of polyphenolic compounds found in plants, have gained attention for their diverse pharmacological activities, including their potential to mitigate carcinogenesis and tumorigenesis in liver cancers. Methods: This review synthesizes findings from studies investigating the impact of flavonoids on liver cancer, focusing on the HepG2 cell line. We explore flavonoid subtypes and their therapeutic roles, including their antioxidant, anti-inflammatory, anti-angiogenic, and cytotoxic properties. Research on mitochondrial function in cancer cells and how flavonoids influence mitochondrial activity in the HepG2 cell line is also assessed. Results: Flavonoids demonstrated significant antioxidant properties by modulating reactive oxygen species (ROS) levels and maintaining mitochondrial homeostasis in HepG2 cells. Key flavonoids, including quercetin, naringenin, and kaempferol, exhibited strong anti-inflammatory and anti-angiogenic effects. Furthermore, cytotoxic flavonoids induced apoptosis in HepG2 cells through mitochondrial disruption and ROS generation, with certain compounds showing selective toxicity to cancer cells. Conclusion: Flavonoids exhibit promising therapeutic potential in liver cancer by targeting oxidative stress, inflammation, and angiogenesis while promoting apoptosis in HepG2 cells. Their ability to modulate mitochondrial function positions them as potent agents for further investigation in liver cancer therapy.

A case of drug-induced liver injury after the administration of tocilizumab for adult Still's disease

A case of drug-induced liver injury after the administration of tocilizumab for adult Still's disease

Glucocorticoid efficacy and treatment strategies for drug-induced liver injury: a literature review.

Drug-induced liver injury (DILI) is an adverse reaction to drugs and their metabolites. The activation of adaptive immune and inflammatory responses plays an important role in the pathogenesis of DILI. Glucocorticoids (GCs) have powerful anti-inflammatory and immunosuppressive effects and have been used to treat a variety of immune-mediated liver diseases. Due to the important role of the immune system in DILI, GCs are widely used in the clinical treatment of DILI; however, whether they are beneficial to patients remains controversial. There is no uniform standard for the timing, dosage, and population selection of GCs, which mainly depend on the clinician's experience. Therefore, elucidating whether GCs are beneficial for patients with DILI is an urgent clinical problem. Our review summarizes the recent literature and discusses the clinical efficacy, applicable population, application timing, and efficacy of GCs in special types of DILI, providing a reference for the clinical application of GCs.

No causal relationship between serum vitamin D levels and alcoholic liver disease: a two-sample bidirectional Mendelian randomization study.

Numerous observational studies have presented an association between Vitamin D (VD) and Alcoholic Liver Disease (ALD). However, sufficient evidence from Randomized Controlled Trials (RCTs) substantiating this correlation is scarce, thus leaving the causality of this relationship ambiguous. To overcome the shortcomings of traditional observational studies, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal relationship between VD and ALD. We utilized summary statistics datasets from Genome-Wide Association Studies (GWAS) for VD and ALD. We selected genetic instruments that measure circulating VD levels (n = 64,979), and retrieved ALD statistics from GWASs, inclusive of 1,416 cases and 217,376 healthy controls, while excluding chronic liver diseases such as nonalcoholic fatty liver disease, toxic liver disease, and viral hepatitis. Subsequent, MR analyses were performed to obtain effect estimates using inverse variance weighted (IVW) random effect models. Cochran's Q statistic and MR-Egger regression intercept analyses were used to assess pleiotropy. Sensitivity analyses using the MR Egger, weighted median, simple mode, and weighted mode methods were also performed. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed. In IVW, our MR analysis incorporated 21 independent SNPs, circulating VD levels had no causal effect on ALD [OR = 0.624 (0.336-1.160), p = 0.136] and ALD had no causal effect on circulating VD [OR = 0.997 (0.986-1.008), p = 0.555]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results. This study provides the causal relationship between genetically predicted circulating Vitamin D levels and ALD and provides new insights into the genetics of ALD.

Design and synthesis of a novel chiral photoacoustic probe and accurate imaging detection of hydrogen peroxide in vivo.

Nanocatalytic medicine, which aims to accurately target and effectively treat tumors through intratumoral in situ catalytic reactions triggered by tumor-specific environments or markers, is an emerging technology. However, the relative lack of catalytic activity of nanoenzymes in the tumor microenvironment (TME) has hampered their use in biomedical applications. Therefore, it is crucial to develop a highly sensitive probe that specifically responds to the TME or disease markers in the TME for precision diagnosis and treatment of diseases. In this work, a chiral photoacoustic (PA) nanoprobe (D/L-Ce@MoO3) based on the H2O2-catalyzed TME activation reaction was constructed in a one-step method using D-cysteine (D-Cys) or L-cysteine (L-Cys), polymolybdate, and cerium nitrate as raw materials. The designed and synthesized D/L-Ce@MoO3 chiral nanoprobe can perform in situ, non-invasive, and precise imaging of pharmacological acute liver injury. In vivo and in vitro experiments have shown that the D/L-Ce@MoO3 probe had chiral properties, the CD signal decreased upon reaction with H2O2, and the absorption and PA signals increased with increasing H2O2 concentration. This is because of the catalytic reaction between Ce ions doped in the nanoenzyme and the high expression of H2O2 caused by drug-induced liver injury to produce ·OH, which has a strong oxidizing property to kill tumor cells and destroy the Mo-S bond in the probe, thus converting the chiral probe into an achiral polyoxometalate (POM) with PA signal.