Drug-induced Hepatotoxicity Research Articles

Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity.

Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium which causes tuberculosis (TB). TB control programmes are facing threats from drug resistance. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains need longer and more expensive treatment with many medications resulting in more adverse effects and decreased chances of treatment outcomes. The World Health Organization (WHO) has emphasised the development of not just new individual anti-TB drugs, but also novel medication regimens as an alternative treatment option for the drug-resistant Mtb strains. Many plants, as well as marine creatures (sponge; Haliclona sp.) and fungi, have been continuously used to treat TB in various traditional treatment systems around the world, providing an almost limitless supply of active components. Natural products, in addition to their anti-mycobacterial action, can be used as adjuvant therapy to increase the efficacy of conventional anti-mycobacterial medications, reduce their side effects, and reverse MDR Mtb strain due to Mycobacterium's genetic flexibility and environmental adaptation. Several natural compounds such as quercetin, ursolic acid, berberine, thymoquinone, curcumin, phloretin, and propolis have shown potential anti-mycobacterial efficacy and are still being explored in preclinical and clinical investigations for confirmation of their efficacy and safety as anti-TB medication. However, more high-level randomized clinical trials are desperately required. The current review provides an overview of drug-resistant TB along with the latest anti-TB medications, drug-induced hepatotoxicity and oxidative stress. Further, the role and mechanisms of action of first and second-line anti-TB drugs and new drugs have been highlighted. Finally, the role of natural compounds as anti-TB medication and hepatoprotectantshave been described and their mechanisms discussed.

Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study.

Anti-tuberculosis drug-induced hepatotoxicity can result from genetic polymorphism of the isoniazid (INH) metabolizing enzyme. This study aimed to determine the effect of genetic polymorphism of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genes on serum isoniazid level and drug-induced hepatotoxicity. A cross-sectional study was conducted on 120 patients (with and without hepatotoxicity) with pulmonary tuberculosis from June 2019 to April 2022 in Tehran (Iran). High-performance liquid chromatography was used to measure the serum concentration of INH and acetylisoniazid (AcINH). NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Data were analyzed using SPSS software (version 22.0) with independent two-sample t test, Chi square test, or Fisher's exact test. P<0.05 was considered statistically significant. A total of 40 patients showed hepatotoxicity. The risk of anti-tuberculosis drug-induced hepatotoxicity was significantly higher in patients who are slow acetylator (SA) phenotype than in rapid or intermediate acetylator (P<0.001). NAT2*4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of NAT2*5 and NAT2*6 haplotypes and serum INH concentration was significantly higher in patients with hepatotoxicity than in those without (P=0.003, P<0.001, and P<0.001, respectively). NAT2*4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and CYP2E1 C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001). Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of NAT2 SA polymorphism. Determining NAT2 and CYP2E1 genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.

P16-55: Using Metabolomics to Uncover Ontogeny of Drug-Induced Hepatotoxicity and Underlying AOP Mechanisms

P16-55: Using Metabolomics to Uncover Ontogeny of Drug-Induced Hepatotoxicity and Underlying AOP Mechanisms

A semimechanistic pharmacokinetic/pharmacodynamic model for alanine aminotransferase-based hepatotoxicity of methotrexate in paediatric patients with acute lymphoid leukaemia.

Methotrexate (MTX) is recognized for its potential to induce hepatotoxicity, commonly manifested by elevated alanine aminotransferase (ALT) levels. However, the quantitative relationship between the pharmacokinetics (PK) of MTX and ALT-based hepatotoxicity remains unclear. This study aimed to develop a semimechanistic PK/pharmacodynamic (PD) model to characterize the MTX-induced hepatotoxicity based on ALT in paediatric patients with acute lymphoid leukaemia. A retrospective study was conducted on paediatric patients who received high-dose (3-5g/m2 ) MTX treatment. MTX concentrations were assessed at 24-h intervals until the concentration dropped below 0.1μmol/L. ALT concentrations were measured both before and after MTX administration. A population PK model was initially developed, which was later connected to a semimechanistic hepatotoxicity model. The PK model was developed using 354 MTX concentrations obtained from 51 patients, while the PD model was constructed using 379 ALT concentrations collected from 48 patients. The optimal PK model for MTX consisted of a 2-compartment structure, where body surface area served as a covariate for clearance and central volume of distribution. An indirect response model coupled to a liver injury signal transduction model was developed to describe the dynamics of ALT after MTX administration. The drug effect was adequately described by a linear model, exhibiting considerable interoccasion variability for each treatment session. No significant covariates were identified to have an impact on the PD parameters. A semimechanistic model was developed to describe ALT-based hepatotoxicity of MTX, and it has the potential to serve as a valuable tool for characterizing drug-induced hepatotoxicity.

Establishment of UGT1A1-knockout human iPS-derived hepatic organoids for UGT1A1-specific kinetics and toxicity evaluation

Uridine diphosphate glucuronosyltransferases (UGTs) are highly expressed in the liver and are involved in the metabolism of many drugs. In particular, UGT1A1 has a genetic polymorphism that causes decreased activity, leading to drug-induced hepatotoxicity. Therefore, an invitro evaluation system that accurately predicts the kinetics of drugs involving UGT1A1 is required. However, there is no such evaluation system because of the absence of the UGT1A1-selective inhibitor. Here, using human induced pluripotent stem (iPS) cells, genome editing technology, and organoid technology, we generated UGT1A1-knockout human iPS hepatocyte-derived liver organoids (UGT1A1-KO i-HOs) as a model for UGT1A1-specific kinetics and toxicity evaluation. i-HOs showed higher gene expression of many drug-metabolizing enzymes including UGT1A1 than human iPS cell-derived hepatocyte-like cells (iPS-HLCs), suggesting that hepatic organoid technology improves liver functions. Wild-type (WT) i-HOs showed similar levels of UGT1A1 activity to primary human (cryopreserved) hepatocytes, while UGT1A1-KO i-HOs completely lost the activity. Additionally, to evaluate whether this model can be used to predict drug-induced hepatotoxicity, UGT1A1-KO i-HOs were exposed to SN-38, the active metabolite of irinotecan, an anticancer drug, and acetaminophen and confirmed that these cells could predict UGT1A1-mediated toxicity. Thus, we succeeded in generating model cells that enable evaluation of UGT1A1-specific kinetics and toxicity.

Shifting perspectives in liver diseases after kidney transplantation.

Liver diseases after kidney transplantation range from mild biochemical abnormalities to severe hepatitis or cirrhosis. The causes are diverse and mainly associated with hepatotropic viruses, drug toxicity and metabolic disorders. Over the past decade, the aetiology of liver disease in kidney recipients has changed significantly. These relates to the use of direct-acting antiviral agents against hepatitis C virus, the increasing availability of vaccination against hepatitis B and a better understanding of drug-induced hepatotoxicity. In addition, the emergence of the severe acute respiratory syndrome coronavirus 2 pandemic has brought new challenges to kidney recipients. This review aims to provide healthcare professionals with a comprehensive understanding of recent advances in the management of liver complications in kidney recipients and to enable them to make informed decisions regarding the risks and impact of liver disease in this population.

Machine Learning-Based Prediction of Drug-Induced Hepatotoxicity: An OvA-QSTR Approach.

Drug-induced hepatotoxicity, also known as drug-induced liver injury (DILI), is among the possible adverse effects of pharmacotherapy. This clinical condition is accepted as one of the factors leading to patient mortality and morbidity. The LiverTox database was built by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to predict potential liver damage from medications and take appropriate precautions. The database has classified medicines into seven risk categories (A, B, C, D, E, E*, and X) to avoid medicine-induced liver toxicity. The hepatic damage risk decreases from group A to group E. This study did not include the E* and X classes because they contained unverified and unknown data groups. Our study aims to predict potential liver damage of new drug molecules without using experimental animals. We predict which of the LiverTox risk category drugs with unknown liver toxicity potential will fall into using our one-vs-all quantitative structure-toxicity relationship (OvA-QSTR) model. Our dataset, consisting of 678 organic drug molecules from different pharmacological classes, was collected from LiverTox. The OvA-QSTR models implemented by Bayesian Network (BayesNet) performed well based on the selected descriptors, with the precision-recall curve (PRC) areas ranging from 0.718 to 0.869. Our OvA-QSTR models provide a reliable premarketing risk evaluation of pharmaceutical-induced liver damage potential and offer predictions for different risk levels in DILI.

Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.

Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 μg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 μM Trolox eq/mL juice, 718.95-3749.47 μM Trolox eq/mL juice, and 2304.74-4390.32 μM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.

Cell-Membrane-Localizing Fluorescence Probes for Aminopeptidase N.

Aminopeptidase N (APN), a transmembrane ectoenzyme, plays multifunctional roles in cell survival and migration, angiogenesis, blood pressure regulation, and viral uptake. Abnormally high levels of the enzyme can be found in some tumors and injured liver and kidney. Therefore, noninvasive detection methods for APN are in demand for diagnosing and studying the associated diseases, leading to two dozen activatable small-molecule probes reported up to date. All of the known probes, however, analyze the enzyme activity by monitoring fluorescent molecules inside cells, despite the enzymatic reaction taking place on the outer cell membrane. In this case, different cell permeability and enzyme kinetics can cause false signal data. To address this critical issue, we have developed two cell-membrane-localizing APN probes whose enzymatic products also localize the outer cell membrane. The probes selectively respond to APN with ratiometric fluorescence signal changes. A selected probe, which has two-photon imaging capability, allowed us to determine the relative APN levels in various organ tissues for the first time: 4.3 (intestine), 2.1 (kidney), 2.7 (liver), 3.2 (lung), and 1.0 (stomach). Also, a higher APN level was observed from a HepG2-xenograft mouse tissue in comparison with the normal tissue. Furthermore, we observed a significant APN level increase in the mouse liver of a drug (acetaminophen)-induced liver injury model. The probe thus offers a reliable means for studying APN-associated biology including drug-induced hepatotoxicity simply by ratiometric imaging.

Size-Transformable Superoxide-Triggered Nanoreporters for Crosstalk-Free Dual Fluorescence/Chemiluminescence Imaging and Urinalysis in Living Mice.

Chemiluminescence imaging has been recognized as a valuable tool for ultrasensitive detection of physio-pathological events through elimination of background autofluorescence. However, most chemiluminescent nanoprobes suffer from shallow imaging depths and slow clearance from living bodies, which impede their use in clinical settings. We herein report size-transformable nanoreporters (ADN1 and ADN2) that could be activated at disease site by superoxide anion (O2 ⋅- ) to trigger nanostructure disassembly into renal excretable fluorescent fragments as well as chemiluminescence turn-on for crosstalk-free duplex chemo-fluorescence imaging and in vitro urinalysis. In peritonitis mouse model, we demonstrate that the representative nanoreporter ADN1 spontaneously accumulates at the disrupted peritoneum and is cleaved by upregulated O2 ⋅- to initiate depolymerization and result in red chemiluminescence at 620 nm, enabling sensitive detection of peritonitis at least 19 h earlier than gold standard histological assays. Additionally, the incorporation of a near-infrared (NIR) dye into ADN1 results in ADN2 exhibiting intense and red-shifted chemiluminescence at ≈800 nm, which permits early detection of deeply seated diseases such as drug-induced hepatotoxicity. This study thus showcases a modular design strategy that is not only applicable to developing versatile chemiluminescent nanoprobes with switchable pharmacokinetics for early disease diagnosis, but also promising for future clinical translations.

Mechanistic Understanding of Idiosyncratic Drug-Induced Hepatotoxicity Using Co-Cultures of Hepatocytes and Macrophages.

Hepatotoxicity or drug-induced liver injury (DILI) is a major safety issue in drug development as a primary reason for drug failure in clinical trials and the main cause for post-marketing regulatory measures like drug withdrawal. Idiosyncratic DILI (iDILI) is a patient-specific, multifactorial, and multicellular process that cannot be recapitulated in current in vitro models; thus, our major goal is to develop and fully characterize a co-culture system and to evaluate its suitability for predicting iDILI. For this purpose, we used human hepatoma HepG2 cells and macrophages differentiated from a monocyte cell line (THP-1) and established the appropriate co-culture conditions for mimicking an inflammatory environment. Then, mono-cultures and co-cultures were treated with model iDILI compounds (trovafloxacin, troglitazone) and their parent non-iDILI compounds (levofloxacin, rosiglitazone), and the effects on viability and the mechanisms implicated (i.e., oxidative stress induction) were analyzed. Our results show that co-culture systems including hepatocytes (HepG2) and other cell types (THP-1-derived macrophages) help to enhance the mechanistic understanding of iDILI, providing better hepatotoxicity predictions.

Early drug-induced hepatotoxicity in newly diagnosed HIV-positive patients on ARV therapy: A retrospective follow-up study of liver function profiles

Antiretroviral therapy (ART) is a primary therapeutic modality for managing individuals with Human Immunodeficiency Virus (HIV) infection, and its efficacy has been established. However, the safety profiles of ART need to be continually monitored, including early elevated liver function test (LFT) after antiretroviral (ARV) initiation. This study aimed to assess the incidence of abnormal LFT among HIV-positive patients receiving initial ARV and to identify factors associated with abnormal LFT. A retrospective cohort study without a control group summarised medical records from Dr Sardjito General Hospital, Yogyakarta between January 2014 and December 2021. The study subjects were adult HIV patients taking their first ARV and underwent follow-up visits for at least two weeks. Study outcomes were LFT levels, abnormal LFT, and factors associated with abnormal LFT during follow-up visits at 2 wk, 6 mo, and 12 mo. Univariate and multivariate analyses will be performed with a significance level of p&lt;0.05. A total of 137 subjects with 203 visits were retrieved from medical records. The subjects' mean age was 33.4 years, predominantly male, younger, unmarried, in the early stage of HIV infection, and without comorbidities. The findings showed a significant increase in alanine transaminase (ALT) at all three follow-up visits: 2 wk (p=0.02), 6 mo (p=0.003), 12 mo (p=0.001) and an increase in aspartate aminotransferase (AST) after 6 mo (p=0.007) and 12 mo (p=0.04). Abnormal LFT levels (AST and/or ALT) were observed in 23.4% of patients after a normal baseline, with ALT increase being more common. Furthermore, homosexuality was identified as a significant independent factor associated with abnormal LFT (AOR=3.1; 95% CI 1.27-7.51; p=0.01). The findings indicate exceptionally elevated LFT levels and the occurrence of abnormal LFTs among HIV-positive patients initiating ARVs. The increase in abnormal LFTs was significantly associated with patients identifying as homosexual, where hepatitis co-infection may be a contributing factor. The limited study design and measured variables warrant further investigation.

Predicting Valproate-Induced Liver Injury Using Metabolomic Analysis of Ex Ovo Chick Embryo Allantoic Fluid.

The use of sensitive animals in toxicological studies tends to be limited. Even though cell culture is an attractive alternative, it has some limitations. Therefore, we investigated the potential of the metabolomic profiling of the allantoic fluid (AF) from ex ovo chick embryos to predict the hepatotoxicity of valproate (VPA). To this end, the metabolic changes occurring during embryo development and following exposure to VPA were assessed using 1H-NMR spectroscopy. During embryonic development, our findings indicated a metabolism progressively moving from anaerobic to aerobic, mainly based on lipids as the energy source. Next, liver histopathology of VPA-exposed embryos revealed abundant microvesicles indicative of steatosis and was metabolically confirmed via the determination of lipid accumulation in AF. VPA-induced hepatotoxicity was further demonstrated by (i) lower glutamine levels, precursors of glutathione, and decreased β-hydroxybutyrate, an endogenous antioxidant; (ii) changes in lysine levels, a precursor of carnitine, which is essential in the transport of fatty acids to the mitochondria and whose synthesis is known to be reduced by VPA; and (iii) choline accumulation that promotes the export of hepatic triglycerides. In conclusion, our results support the use of the ex ovo chick embryo model combined with the metabolomic assessment of AF to rapidly predict drug-induced hepatotoxicity.

Proinflammatory cytokines VEGFA, IL-6, IL-8 as markers of hepatotoxicity after COVID-19

The mechanism of hepatocellular liver damage after COVID-19 is a multifactorial process. The most widely discussed causes are cytolytic liver damage due to the inflammatory response after COVID-19, drug-induced hepatotoxicity and direct cytotoxic effect of the virus. There are observations that SARSCoV-2 infection causes hepatitis B virus reactivation, but little has been described about the interaction between hepatitis C virus and SARS-CoV-2. The course of coronavirus infection is associated with marked expression of proinflammatory cytokines, participants in the multisystem inflammatory response, IL-1β, IL-6, IL-8, IL-18, MCP-1, TNFα, which contribute significantly to the observed early and late liver function impairment. The aim of the study was to evaluate the role of proinflammatory cytokines (VEGFA, IL-8, IL-6, MCP-1, TNFα, IL-18) as additional markers of hepatotoxicity after COVID-19. The study was performed between March and August 2022. Patients were divided into 2 groups: Group 1 – with increased aminotransferases against the background of treatment from COVID-19 and/or in the following 3-6 months after the disease without viral liver damage (n = 42), Group 2 – patients with co-infection (chronic viral hepatitis C (HCV) and COVID-19 (n = 26). The levels of cytokines – VEGF-A, IL-6, IL-8, MCP-1, IL-18, TNFα in blood serum were estimated by enzyme immunoassay method. Statistical analysis was performed using StatTech v. 3.1.4. The results of the study revealed a comparable increase in the level of transaminases and C-reactive protein in both groups, significantly different from the reference values. Direct correlations of moderate strength (linear Spearman correlation) were found between the following cytokines: TNFα-MCP-1 (R = 0.559; p = 0.001), TNFα-VEGFA (R = 0.400; p = 0.002), TNFα-IL-6 (R = 0.503; p = 0.001). We diagnosed a significant increase in serum VEGFA levels in group 1 patients (hepatotoxicity after COVID-19) (Me (Q0.25-Q0.75): 522 (250 to 1002), p = 0.001) and in group 2 patients (HCV + COVID-19) (Me 1196, Q0.25-Q0.75: (73 to 432). Similar trend with the level of IL-6, IL-8, exceeding the values of cytokines in healthy donors and significantly higher than in group 2 patients. Identified correlations between inflammatory cytokines prove unidirectional changes in the functioning of the regulatory network controlling immune virus-induced reactions.

Endoplasmic Reticulum-Targeted Carbon Monoxide Photoreleaser for Drug-Induced Hepatotoxicity Remediation.

The alleviation of drug-induced liver injury has been a long-term public health concern. Growing evidence suggests that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of drug-induced hepatotoxicity. Therefore, the inhibition of ER stress has gradually become one of the important pathways to alleviate drug-induced liver injury. In this work, we developed an ER-targeted photoreleaser, ERC, for controllable carbon monoxide (CO) release with a near-infrared light trigger. By employing peroxynitrite (ONOO-) as an imaging biomarker of hepatotoxicity, the remediating effect of CO was mapped upon drug acetaminophen (APAP) challenge. The direct and visual evidence of suppressing oxidative and nitrosative stress by CO was obtained both in living cells and in mice. Additionally, the ER stress inhibiting the effect of CO was verified during drug-induced hepatotoxicity. This work demonstrated that CO may be employed as a potent potential antidote for APAP-related oxidative and nitrative stress remediation.

DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia: is there a causal relationship?

Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.

Modeling Based on Ensemble Learning Methods for Detection of Diagnostic Biomarkers from LncRNA Data in Rats Treated with Cis-Platinum-Induced Hepatotoxicity.

The first aim of this study is to perform bioinformatic analysis of lncRNAs obtained from liver tissue samples from rats treated with cisplatin hepatotoxicity and without pathology. Another aim is to identify possible biomarkers for the diagnosis/early diagnosis of hepatotoxicity by modeling the data obtained from bioinformatics analysis with ensemble learning methods. In the study, 20 female Sprague-Dawley rats were divided into a control group and a hepatotoxicity group. Liver samples were taken from rats, and transcriptomic and histopathological analyses were performed. The dataset achieved from the transcriptomic analysis was modeled with ensemble learning methods (stacking, bagging, and boosting). Modeling results were evaluated with accuracy (Acc), balanced accuracy (B-Acc), sensitivity (Se), specificity (Sp), positive predictive value (Ppv), negative predictive value (Npv), and F1 score performance metrics. As a result of the modeling, lncRNAs that could be biomarkers were evaluated with variable importance values. According to histopathological and immunohistochemical analyses, a significant increase was observed in the sinusoidal dilatation and Hsp60 immunoreactivity values in the hepatotoxicity group compared to the control group (p < 0.0001). According to the results of the bioinformatics analysis, 589 lncRNAs showed different expressions in the groups. The stacking model had the best classification performance among the applied ensemble learning models. The Acc, B-Acc, Se, Sp, Ppv, Npv, and F1-score values obtained from this model were 90%, 90%, 80%, 100%, 100%, 83.3%, and 88.9%, respectively. lncRNAs with id rna-XR_005492522.1, rna-XR_005492536.1, and rna-XR_005505831.1 with the highest three values according to the variable importance obtained as a result of stacking modeling can be used as predictive biomarker candidates for hepatotoxicity. Among the ensemble algorithms, the stacking technique yielded higher performance results as compared to the bagging and boosting methods on the transcriptomic data. More comprehensive studies can support the possible biomarkers determined due to the research and the decisive results for the diagnosis of drug-induced hepatotoxicity.

Drug-induced Hepatotoxicity Cases in Some Tertiary Care Hospitals of Andhra Pradesh, India: A Retrospective Study

Pharmaceutical preparations are currently significant contributors to liver illness, in which hepatotoxicity being the most common cause of Acute liver failure .The liver is a vital organ, its strategic location and multidimensional functions support almost every other organ in the body. It is the main organ for metabolism, elimination of metabolic products and hepatotoxicity is a potential adverse effect for most of the drugs particularly Anti-tubercular drugs, general anaesthetics, paracetamol and some Anti-cancer drugs. Liver sometimes can be damaged by some chemicals called hhepatotoxins such as galactosamine and chloroform. Moreover steroids, vaccines and anti-viral drugs which are used as treatment option for liver diseases, may produce adverse effects especially after chronic administration. The main objective of our study is to assess the frequency of drugs causing the severity of Hepatotoxicity in patients in a tertiary care hospitals. A prospective observational study was carried out in 3 different tertiary care hospitals at Andhra Pradesh, India. It was found that males are more prone to hepatotoxicity compared to females, as well as the age group 25-64 years (67%) are more hepatotoxic compared to above 65years (15%) age group. So there is a need of awareness in patients and physicians to consider the drug induced hepatotoxicity while giving the treatment, in which most of the cases it was being left unconsidered and finally leading to hepatotoxicity starting with mild and moderate stages.

Prediction of drug-induced hepatotoxicity based on histopathological whole slide images.

Liver is an important metabolic organ in human body and is sensitive to toxic chemicals or drugs. Adverse reactions caused by drug hepatotoxicity will damage the liver and hepatotoxicity is the leading cause of removal of approved drugs from the market. Therefore, it is of great significance to identify liver toxicity as early as possible in the drug development process. In this study, we developed a predictive model for drug hepatotoxicity based on histopathological whole silde images (WSI) which are the by-product of drug experiments and have received little attention. To better represent the WSIs, we constructed a graph representation for each WSI by dividing it into small patches, taking sampled patches as nodes and calculating the correlation coefficients between node features as the edges of the graph structure. Then a WSI-level graph convolutional network (GCN) was built to effectively extract the node information of the graph and predict the toxicity. In addition, we introduced a gated attention global context vector (gaGCV) to combine the global context to make node features to contain more comprehensive information. The results validated on rat liver in vivo data from the Open TG-GATES show that the use of WSI for the prediction of toxicity is feasible and effective.

Antioxidant-Based Preventive Effect of Phytochemicals on Anticancer Drug-Induced Hepatotoxicity.

Significance: Drug-induced liver injury (DILI) or hepatotoxicity has been a hot issue to overcome on the safety and physiological function of the liver, since it is known to have biochemical, cellular, immunological, and molecular alterations in the liver mainly induced by alcohol, chemicals, drugs, heavy metals, and genetic factors. Recently efficient therapeutic and preventive strategies by some phytochemicals are of interest, targeting oxidative stress-mediated hepatotoxicity alone or in combination with anticancer drugs. Recent Advances: To assess DILI, the variety of in vitro and in vivo animal models has been developed mainly by using carbon tetrachloride, d-galactosamine, acetaminophen, and lipopolysaccharide. Also, the mechanisms on hepatotoxicity by several drugs and herbs have been explored in detail. Recent studies reveal that antioxidants including vitamins and some phytochemicals were reported to prevent against DILI. Critical Issues: Antioxidant therapy with some phytochemicals is noteworthy, since oxidative stress is critically involved in DILI via production of chemically reactive oxygen species or metabolites, impairment of mitochondrial respiratory chain, and induction of redox cycling. Future Directions: For efficient antioxidant therapy, DILI susceptibility, Human Leukocyte Antigen genetic factors, biomarkers, and pathogenesis implicated in hepatotoxicity should be further explored in association with oxidative stress-mediated signaling, while more randomized preclinical and clinical trials are required with optimal safe doses of drugs and/or phytochemicals alone or in combination for efficient clinical practice along with the development of advanced DILI diagnostic tools. Antioxid. Redox Signal. 38, 1101-1121.