Dataset Information

Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats.

ABSTRACT: Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g/kg), bromobenzene (0.4 g/kg), and carbon tetrachloride (0.3 g/kg), to identify early perturbations in liver metabolism after a single acute exposure dose. We measured changes in liver genes and plasma metabolites at two time points (5 and 10 h) and used genome-scale metabolic models to identify commonalities in liver responses across the three toxicants. We found strong correlations for gene and metabolic profiles between the toxicants, indicative of similarities in the liver response to toxicity. We identified several injury-specific pathways in lipid and amino acid metabolism that changed similarly across the three toxicants. Our findings suggest that several plasma metabolites in lipid and amino acid metabolism are strongly associated with the progression of liver toxicity, and as such, could be targeted and clinically assessed for their potential as early predictors of acute liver toxicity.

SUBMITTER: Pannala VR

PROVIDER: S-EPMC7663358 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats.

Pannala Venkat R VR Estes Shanea K SK Rahim Mohsin M Trenary Irina I O'Brien Tracy P TP Shiota Chiyo C Printz Richard L RL Reifman Jaques J Shiota Masakazu M Young Jamey D JD Wallqvist Anders A

International journal of molecular sciences 20201104 21

Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g/kg), bromobenzene (0.4 g/kg), and carbon tetrachloride ( ...[more]

PMID: 33158035

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Project description:Environmental toxicants like microcystins are known to adversely impact liver physiology and lead to the increased risk for abnormal liver function and even liver carcinoma. Chaga mushroom (Inonotus obliquus) is reported for various properties mainly antibacterial, antiallergic, anti-inflammatory, antioxidant, and anticancer properties. This study was aimed to assess the effect microcystin (MC-LR) on histopathology of liver in mice and a preventive measure by using aqueous extract of Inonotus obliquus (IOAE). Adult Balb/c mice were administered with MC-LR at 20 μg/kg body weight, per day, intraperitoneal (i.p.) for 4 weeks. IOAE was treated to one group of MC-LR mice at 200 mg/kg body weight, per oral, for 4 weeks. Histological staining for liver structural details and biochemical assays for functions were assessed. The results of the study showed that MC-LR drastically reduced the body weight of mice which were restored close to the range of control by IOAE treatment. MC-LR exposed mice showed 1.9, 1.7 and 2.2-fold increase in the levels of SGOT, SGPT and LDH which were restored by IOAE treatment as compared to control (one-fold). MC-LR exposed mice showed reduced level of GSH (19.83 ± 3.3 μM) which were regained by IOAE treatment (50.83 ± 3.0 μM). Similar observations were noted for catalase activity. Histological examinations show that MC-LR exposed degenerative changes in the liver sections which were restored by IOAE supplementation. The immunofluorescence analysis of caspase-3 counterstained with DAPI showed that MC-LR led to the increased expression of caspase-3 which were comparatively reduced by IOAE treatment. The cell viability decreased on increasing the concentration of MC-LR with 5% cell viability at concentration of 10 μg MC-LR/mL as that of control 100% Cell viability. The IC50 was calculated to be 3.6 μg/ml, indicating that MC-LR is chronic toxic to AML12 mouse hepatocytes. The molecular docking interaction of NF-κB-NIK with ergosterol peroxidase showed binding interaction between the two and showed the plausible molecular basis for the effects of IOAE in MC-LR induced liver injury. Collectively, this study revealed the deleterious effects of MC-LR on liver through generation of oxidative stress and activation of caspase-3, which were prevented by treatment with IOAE.

Dataset Information

Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats.

Publications

Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats.

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