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High Content Screening Analysis to Evaluate the Toxicological Effects of Harmful and Potentially Harmful Constituents HPHC
Published on: May 10, 2016
Metabolomics revealed the toxicity of cationic liposomes in HepG2 cells using UHPLC-Q-TOF/MS and multivariate data
Jing Yu1, Hai Zhang2, Ying Li1
1Department of Pharmacy, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
Abstract:
Cationic liposomes (CLs) are novel nonviral vectors widely used for delivering drugs or genes. However, applications of CLs are largely hampered by their cytotoxicity, partly because the potential mechanism underlying the cytotoxicity of CLs remains unclear. The aim of the present study was to explore the underlying mechanism of cytotoxicity induced by CLs on HepG2 cells. Differential metabolites were identified and quantified using ultra-liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The toxicity of CLs on HepG2 cells was evaluated by multivariate data analysis and statistics. Additionally, CCK-8 assay, heatmap, pathway and co-expression network were carried out to explore the relations between the metabolites and the pathways. The results showed a dose-dependent toxic effect of CLs on HepG2 cells, with an IC50 value of 119.9 μg/mL. Multivariate statistical analysis identified 42 potential metabolites between CLs exposure and control groups. Pathway analysis showed significant changes in pathways involving amino acid metabolism, energy metabolism, lipid metabolism and oxidative stress in the CLs exposure group vs the control group. Metabolites related to the above-mentioned pathways included phenylalanine, methionine, creatine, oxalacetic acid, glutathione, oxidized glutathione, choline phosphate and several unsaturated fatty acids, indicating that cells were disturbed in amino acid metabolism, energy and lipid supply when CLs exposure-induced injury occurred. It is concluded that CLs may induce cytotoxicity by enhancing reactive oxygen species in vitro, affect the normal process of energy metabolism, disturb several vital signaling pathways and finally induce cell death.
Insights
Cationic liposomes (CLs) show dose-dependent toxicity in HepG2 cells. CLs induce cell death by disrupting amino acid, energy, and lipid metabolism, alongside oxidative stress.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Cationic liposomes (CLs) are promising nonviral vectors for drug and gene delivery.
- Cytotoxicity of CLs limits their clinical application, with the underlying mechanisms poorly understood.
Purpose of the Study:
- To elucidate the mechanism of cytotoxicity induced by CLs in HepG2 cells.
- To identify metabolic alterations associated with CLs exposure.
Main Methods:
- HepG2 cells were exposed to varying concentrations of CLs.
- Metabolomic profiling was performed using ultra-liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS).
- Cell viability was assessed using CCK-8 assays, and pathway analysis was conducted.
Main Results:
- CLs exhibited a dose-dependent cytotoxic effect with an IC50 of 119.9 μg/mL.
- 42 differential metabolites were identified between CLs-exposed and control groups.
- Significant alterations were observed in amino acid metabolism, energy metabolism, lipid metabolism, and oxidative stress pathways.
Conclusions:
- CLs induce cytotoxicity in HepG2 cells, potentially through enhanced reactive oxygen species production.
- CLs disrupt cellular energy metabolism and vital signaling pathways, leading to cell death.
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