scholarly journals Research on the Species Difference of the Hepatotoxicity of Medicine Based on Transcriptome

2021 ◽  
Vol 12 ◽  
Author(s):  
Ziying Xu ◽  
Qianjun Kang ◽  
Zihui Yu ◽  
Lichun Tian ◽  
Jingxuan Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Animal Models ◽  
Liver Injury ◽  
Drug Toxicity ◽  
Species Difference ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Rats And Mice

In recent years, several drugs have been withdrawn from use by regulatory bodies owing to hepatotoxicity; therefore, studies on drug-induced liver injury (DILI) are being actively pursued. Most studies evaluating DILI use rats or mice as animal models to determine drug toxicity; however, the toxicity of a drug can vary between rats or mice. These inconsistencies in in vivo studies among different animal models affect the extrapolation of experimental results to humans. Thus, it is particularly important to choose the most suitable animal model to determine drug hepatotoxicity owing to the genomic differences between rats and mice resulting from evolution. In this study, genome-wide transcriptome analysis was used to explore hepatotoxicity caused by differences in species. Our findings provide the preclinical basis to further study the mechanisms of drug hepatotoxicity and aid in the selection of animal models to determine drug safety. We used murine models (Sprague-Dawley and Wistar rats, ICR and Kunming mice) in this study and by using transcriptome sequencing with the differentially expressed genes in rat and mouse livers as the entry point, we explored the mechanism of oxidative stress and the difference in gene expression in the lipid-metabolism pathway between rats and mice. The clinically established hepatotoxic drugs, fructus psoraleae and acetaminophen were used to validate our study. Using pathological studies, we confirmed that oxidative stress in mice was more serious than that in rats, and that Kunming mice were more suited for the study of oxidative stress-related DILI. The validity of our findings was further verified based on gene expression. Thus, our study could serve as a valuable reference for the evaluation of potential preclinical hepatotoxicity. Moreover, it could be used in the prediction and early diagnosis of drug-induced liver injury caused by traditional Chinese medicine or synthetic drugs, thereby providing a new avenue for drug-toxicity studies.

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

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
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.

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

2020 ◽  
Vol 48 (8) ◽  
pp. 994-1007
Author(s):  
Timothy P. LaBranche ◽  
Anna K. Kopec ◽  
Srinivasa R. Mantena ◽  
Brett D. Hollingshead ◽  
Andrew W. Harrington ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Pharmaceutical Industry ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Sd Rats ◽  
Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

scholarly journals Diverse approaches to predicting drug-induced liver injury using gene-expression profiles

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
G. Rex Sumsion ◽  
Michael S. Bradshaw ◽  
Jeremy T. Beales ◽  
Emi Ford ◽  
Griffin R. G. Caryotakis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Injury ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals Utilization of Causal Reasoning of Hepatic Gene Expression in Rats to Identify Molecular Pathways of Idiosyncratic Drug-Induced Liver Injury

2013 ◽  
Vol 137 (1) ◽  
pp. 234-248 ◽  
Author(s):  
Daphna Laifenfeld ◽  
Luping Qiu ◽  
Rachel Swiss ◽  
Jennifer Park ◽  
Michael Macoritto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Injury ◽  
Causal Reasoning ◽  
Molecular Pathways ◽  
Hepatic Gene Expression ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals Prediction of Alternative Drug-Induced Liver Injury Classifications Using Molecular Descriptors, Gene Expression Perturbation, and Toxicology Reports

2021 ◽  
Vol 12 ◽  
Author(s):  
Wojciech Lesiński ◽  
Krzysztof Mnich ◽  
Witold R. Rudnicki
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Liver Injury ◽  
Cell Lines ◽  
Predictive Models ◽  
Molecular Descriptors ◽  
Chemical Properties ◽  
Human Cell Lines ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Motivation: Drug-induced liver injury (DILI) is one of the primary problems in drug development. Early prediction of DILI, based on the chemical properties of substances and experiments performed on cell lines, would bring a significant reduction in the cost of clinical trials and faster development of drugs. The current study aims to build predictive models of risk of DILI for chemical compounds using multiple sources of information.Methods: Using several supervised machine learning algorithms, we built predictive models for several alternative splits of compounds between DILI and non-DILI classes. To this end, we used chemical properties of the given compounds, their effects on gene expression levels in six human cell lines treated with them, as well as their toxicological profiles. First, we identified the most informative variables in all data sets. Then, these variables were used to build machine learning models. Finally, composite models were built with the Super Learner approach. All modeling was performed using multiple repeats of cross-validation for unbiased and precise estimates of performance.Results: With one exception, gene expression profiles of human cell lines were non-informative and resulted in random models. Toxicological reports were not useful for prediction of DILI. The best results were obtained for models discerning between harmless compounds and those for which any level of DILI was observed (AUC = 0.75). These models were built with Random Forest algorithm that used molecular descriptors.

scholarly journals Crocus sativus L. Extract Containing Polyphenols Modulates Oxidative Stress and Inflammatory Response against Anti-Tuberculosis Drugs-Induced Liver Injury

Plants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 167 ◽  
Author(s):  
Adil Farooq Wali ◽  
Jayachithra Ramakrishna Pillai ◽  
Yusra Al Dhaheri ◽  
Muneeb U. Rehman ◽  
Ambreen Shoaib ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Hepatic Injury ◽  
Standard Dose ◽  
Crocus Sativus ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Response Status ◽  
Crocus Sativus L

The purpose of this study is to analyze the polyphenolic rich extract of Crocus sativus L. petals (CSP) in modulating liver oxidative stress and inflammatory response status against rifampicin isoniazid (INH-RIF) drug-induced liver injury. The INH-RIF was administered for 14 days with varying doses in Wistar rats, while silymarin was administered as standard dose. We report the defensive impacts of CSP against INH-RIF induced liver oxidative stress and proinflammatory cytokine. The CSP treatment at both doses significantly controlled all modulating biochemical hepatic injury indicators and resulted in the attenuation of arbitral INH-RIF damage. The components present in CSP identified by LC–ESI-Q-TOF–MS were found to be flavonoids and fatty acids. It can be inferred that CSP possesses a hepatoprotective capacity against INH-RIF-mediated hepatic injury, which may prove to be a medically beneficial natural product for the management of drug-induced liver injury.

scholarly journals ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins

2021 ◽  
Vol 12 ◽  
Author(s):  
Wen Su ◽  
Mingji Feng ◽  
Yuan Liu ◽  
Rong Cao ◽  
Yiao Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Serum Levels ◽  
Zinc Transporter ◽  
Hepatocyte Proliferation ◽  
Glycogen Depletion ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Cytochrome P450 Family ◽  
Jnk Activation

Zinc transporter 8 (ZnT8) is an important zinc transporter highly expressed in pancreatic islets. Deficiency of ZnT8 leads to a marked decrease in islet zinc, which is thought to prevent liver diseases associated with oxidative stress. Herein, we aimed to investigate whether loss of islet zinc affects the antioxidant capacity of the liver and acute drug-induced liver injury. To address this question, we treated ZnT8 knockout (KO) or wild-type control mice with 300 mg/ kg acetaminophen (APAP) or phosphate-buffered saline (PBS). Unexpectedly, we found that loss of ZnT8 in mice ameliorated APAP-induced injury and was accompanied by inhibition of c-Jun N-terminal kinase (JNK) activation, reduced hepatocyte death, and decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). An increase in hepatic glutathione (GSH) was observed, corresponding to a decrease in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. APAP-induced inflammation and glycogen depletion were alleviated. In contrast, no significant changes were observed in cytochrome P450 family 2 subfamily E member 1 (CYP2E1), the main enzyme responsible for drug metabolism. Elevated levels of hepatic zinc and metallothionein (MT) were also observed, which may contribute to the hepatoprotective effect in ZnT8 KO mice. Taken together, these results suggest that ZnT8 deficiency protects the liver from APAP toxicity by attenuating oxidative stress and promoting hepatocyte proliferation. This study provides new insights into the functions of ZnT8 and zinc as key mediators linking pancreatic and hepatic functions.

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