Drug-induced Liver Injury In Rats Research Articles

Correlation between drug-induced liver injury in rats caused by Xianling Gubao oral preparation and extraction process

In light of the liver injury risk associated with the oral administration of Xianlin Gubao oral preparation, this study compared the differences in liver injury induced by two different extraction processes in rats and explored the correlation between hepatotoxicity and extraction process from the perspective of the differences in the content of the relevant components. Thirty male Sprague-Dawley(SD) rats were randomly divided into a normal group, tablet extract groups of different doses, and capsule extract groups of different doses, with 6 rats in each group. Each group received continuous oral administration for 4 weeks. The assessment of liver injury caused by different extracts was conducted by examining rat body weight, liver function blood biochemical indicators, liver coefficient, and liver pathological changes. In addition, a high-performance liquid chromatography(HPLC) method was established to simultaneously determine the content of icariin, baohuoside I, and bakuchiol in the extracts to compare the differences in the content of these three components under the two extraction processes. The results showed that both extracts caused liver injury in rats. Compared with the normal group, the tablet extract groups, at the studied dose, led to slow growth in body weight, a significant increase in triglyceride levels(P<0.05), a significant decrease in liver-to-brain ratio(P<0.05), and the appearance of hepatic steatosis. The capsule extract groups, at the studied dose, resulted in slow growth in body weight, a significant increase in aspartate aminotransferase levels(P<0.05), a significant decrease in body weight, liver weight, and liver-to-brain ratio(P<0.05), and the presence of hepatic steatosis and inflammatory cell infiltration. In comparison, the capsule extraction process had a higher risk of liver injury. Furthermore, based on the completion of the liquid chromatography method, the content of icariin and baohuoside Ⅰ in the capsule extract groups was 0.83 and 0.81 times that in the tablet extract groups, respectively, while the bakuchiol content in the capsule extract group was 29.80 times that in the tablet extract groups, suggesting that the higher risk of liver injury associated with the capsule extraction process may be due to its higher bakuchiol content. In summary, the differences in rat liver injury caused by the two extracts are closely related to the extraction process. This should be taken into consideration in the formulation production and clinical application.

Tandem mass tag-based proteomics analysis reveals the effects of Guri Gumu-13 pill on drug-induced liver injury

The incidence of drug-induced liver injury (DILI) is second only to viral hepatitis and steatohepatitis in China, and DILI has become a serious public health problem that cannot be ignored. Guri Gumu-13 pill (GRGM) is a traditional Chinese medicine (TCM), which has a protective effect on liver diseases. However, the underlying therapeutic mechanisms of GRGM for DILI are still vague. In this study, the protective effect of GRGM on acetaminophen (APAP)-induced DILI was investigated based on the proteomics clues. The effects of GRGM on APAP-induced DILI in rats were studied using tandem mass tag (TMT)-based quantitative proteomics technology. Besides, western blotting was exerted to verify related proteins. Using the TMT-based quantitative proteomics approach, 237 proteins were identified as regulated in APAP-induced DILI and 58 proteins were regulated by GRGM. The 17 overlapping differentially expressed proteins (DEPs) were identified, and 7 proteins were inversely regulated. Enrichment analysis of KEGG indicated that metabolic pathways, linoleic acid metabolism, and retinol metabolism might be affected in DILI. Next, Cyp2c11, Aldh1a1, and Fads2 were verified with molecular biotechnology. GRGM exerts therapeutic effects through multi-pathways regulation in the treatment of DILI. This work may provide proteomics clues for the continuation of research on DILI treatment with GRGM.

Protective Effect of Dandelion Leaf Water Extracts on APAP-Induced Liver Injury in Rats and Its Mechanism.

with the advent of a large number of drugs in recent years and the aggravation of human aging, drug-induced liver injury is increasing year by year. The protective effect of dandelion extract on acetaminophen (APAP) - induced drug-induced liver injury in rats and its specific mechanism was studied by in vitro cell culture. For this aim,twenty healthy SD rats with the same physiological status were divided into model group and normal group, with 10 rats in each group. The drug-induced liver injury model was made by intragastric administration of 1 g/kg APAP for 14 days. The liver function lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were detected to verify the success of the model. After that, the liver tissues were aseptically isolated from the normal group and APAP model group, and the primary hepatocytes were cultured. They were divided into control group (control), liver injury model group (model), medium-dose dandelion extract group (1mm dlwe) and high dose dandelion extract group (2mm dlwe). The cell proliferation activity was detected by CCK-8 cell proliferation activity kit. Cell samples were collected at 72 hours to detect the contents of AST and ALT in cell supernatant. The contents of oxidative stress-activated oxygen (ROS), reduced glutathione (GSH) and glutathione peroxidase (GSH-Px) were detected by colorimetry, and the apoptosis was detected by flow cytometry. Inflammatory factors, key genes of liver injury, drug metabolic enzymes cytochrome P450 2E1 (CYP2E1), mitogen-activated protein kinase (MAPK) and nuclear transcription factors were detected by RT-PCR- κ B (NF- κ B) P65 signaling pathway-related gene expression level. Finally, the expression of CYP2E1, MAPK and NF-kB signaling pathwayswere analyzed by Western blot. Results showed thatSerum ast, ALT and LDH increased (P<0.05), suggesting that the liver injury model was successful. The hepatocytes in the normal group were oval, flat, evenly distributed and well adhered to the wall. The liver injury model group had more suspended cells, pseudopodia, polygonal and poor growth state. The cells in the medium-dose dandelion extract group (1mm dlwe) and high dose dandelion extract group (2mm dlwe) adhered well, mostly oval, similar to the normal group and grew well. CCK8 found that the cells in the model group decreased significantly, the proliferation activity decreased significantly, the ast, alt, LDH and ROS in the cell supernatant of the model group increased compared with other groups (P<0.05), and the contents of GSH and GSH PX decreased (P < 0.05). Apoptotic cells in the model group increased, and TNF in the model group-α, COX-2, CYP2E1, MAPK, JNK and NF KB p65 increased (P < 0.05). CYP2E1, MAPK and NF KB p65 increased in the model group (P < 0.05).

Oral Phosphatidylcholine Improves Intestinal Barrier Function in Drug-Induced Liver Injury in Rats.

Objective Phosphatidylcholine (PC) is the major surface-active phospholipid and creates a hydrophobic nature to the surface. It has been reported to reverse the progression of liver fibrosis and to improve liver function. The aim of the present study was to evaluate the effects of orally administered PC on intestinal barrier function (IBF) in rats with drug-induced liver injury. Method Rats with carbon tetrachloride- (CCl4-) induced liver injury were treated with 100 mg/kg PC once daily for 21 days. The effects of PC therapy on (i) liver function and portal pressure, (ii) intestinal and hepatic histology, and (iii) plasma endotoxin, diamine oxidase (DAO), and tumour necrosis factor- (TNF-) α levels were investigated. Results PC therapy reduced portal pressure and improved the liver function in CCl4-induced liver injury. In PC-treated liver injury rats, collagen fibres were gradually decreased, while the disordered arrangement of hepatocytes and disorganized hepatic lobules were partially repaired, and inflammatory cell infiltration was decreased in the fibrous tissue. Lower inflammatory cell infiltration in the ileum improved intestinal histology, and reduced serum DAO levels were observed in PC-treated cirrhotic rats. These changes were associated with reduced inflammatory activity, as indicated by decreased serum TNF-α levels and plasma endotoxin levels. Conclusions These results suggest that PC therapy is hepatoprotective and is able to restore IBF and reduce endotoxaemia in rats with drug-induced liver injury.

Comparative gene and protein expression analyses of a panel of cytokines in acute and chronic drug-induced liver injury in rats.

Drug-induced liver injury (DILI) is a significant safety issue associated with medication use, and is the major cause of failures in drug development and withdrawal in post marketing. Cytokines are signaling molecules produced and secreted by immune cells and play crucial roles in the progression of DILI. Although there are numerous reports of cytokine changes in several DILI models, a comprehensive analysis of cytokine expression changes in rat liver injury induced by various compounds has, to the best of our knowledge, not been performed. In the past several years, we have built a public, free, large-scale toxicogenomics database, called Open TG-GATEs, containing microarray data and toxicity data of the liver of rats treated with various hepatotoxic compounds. In this study, we measured the protein expression levels of a panel of 24 cytokines in frozen liver of rats treated with a total of 20 compounds, obtained in the original study that formed the basis of the Open TG-GATEs database and analyzed protein expression profiles combined with mRNA expression profiles to investigate the correlation between mRNA and protein expression levels. As a result, we demonstrated significant correlations between mRNA and protein expression changes for interleukin (IL)-1β, IL-1α, monocyte chemo-attractant protein (MCP)-1/CC-chemokine ligand (Ccl)2, vascular endothelial growth factor A (VEGF-A), and regulated upon activation normal T cell expressed and secreted (RANTES)/Ccl5 in several different types of DILI. We also demonstrated that IL-1β protein and MCP-1/Ccl2 mRNA were commonly up-regulated in the liver of rats treated with different classes of hepatotoxicants and exhibited the highest accuracy in the detection of hepatotoxicity. The results also demonstrate that hepatic mRNA changes do not always correlate with protein changes of cytokines in the liver. This is the first study to provide a comprehensive analysis of mRNA-protein correlations of factors involved in various types of DILI, as well as additional insights into the importance of understanding complex cytokine expression changes in assessing DILI.

Antioxidant and hepatoprotective effects of Garcinia indica fruit rind in antitubercular drug-induced liver injury in rats

Antioxidant and hepatoprotective effects of Garcinia indica fruit rind in antitubercular drug-induced liver injury in rats Vandana S Panda,1 Hardik D Ashar,1 Anita Sharan2 1Department of Pharmacology and Toxicology, Prin KM Kundnani College of Pharmacy, Colaba, Mumbai, India; 2Department of Pathology, Dr DY Patil Medical College, Nerul, Navi Mumbai, India Abstract: The protective effects of aqueous extracts of the fruit rind of Garcinia indica (GIE) in antitubercular drug (ATD)-induced liver injury were investigated in rats. GIE (400 mg/kg and 800 mg/kg) and the reference drug Liv.52 (500 mg/kg) were administered orally for 29 days to ATD (isoniazid 7.5 mg/kg, rifampicin 10 mg/kg, and pyrazinamide 35 mg/kg)-treated rats. GIE attenuated significantly the ATD-elevated levels of aspartate aminotransferase, alanine transaminase, alkaline phosphatase, bilirubin, and malondialdehyde and restored the ATD-depleted levels of glutathione (GSH), superoxide dismutase, catalase, GSH peroxidase, and GSH reductase. The present findings indicate that the hepatoprotective effect of GIE in ATD-induced oxidative damage may be due to its antioxidant activity. Keywords: Garcinia indica fruit, antitubercular drugs, Liv.52, hepatoprotective, antioxidant activity

Effect of Liv.100, an Ayurvedic Formulation on the Erythrocyte Antioxidant Status in Antitubercular Drug-Induced Liver Injury in Rats

Effect of Liv.100, an Ayurvedic Formulation on the Erythrocyte Antioxidant Status in Antitubercular Drug-Induced Liver Injury in Rats