Metabolomic and lipidomic profiling of rat plasma by the single dose administration of two generation of mTOR inhibitors
- Metabolomic and lipidomic profiling of rat plasma by the single dose administration of two generation of mTOR inhibitors
- 정병화; 이현범; 라시드
- mTOR; metabolomics
- Issue Date
- The mammalian target of rapamycin (mTOR) acts as a key regulator of cell growth, metabolism, proliferation and survival and consists with two distinct protein complexes (mTORC1 and mTORC2). Based on the inhibitory properties, mTOR inhibitors are classified into two generation. First generation inhibitors are defined by the ability to inhibit only mTORC1 whereas second generation inhibitors can inhibit both the subunit of mTOR. In this study, rapamycin (sirolimus), and AZD8055 and PP242 were selected as first and second-generation mTOR inhibitors, respectively. The aim of this study is to evaluate and compare the metabolic differences caused by these two generation of mTOR inhibitors after a single oral dose. Rapamycin was administered orally at a dose of 5 mg/kg, whereas, AZD8055 and PP242 were administered at a dose of 20 mg/kg to Sprague Dawley (SD) rats. Blood samples were collected at the time points of 0, 4, 8, 12, 24, and 48 hours, respectively and plasma were separated upon centrifugation. Samples were analyzed through untargeted metabolomics combined with lipidomics approach using ultra-performance liquid chromatography-orbitrap-mass spectrometry (UPLC-Orbitrap-MS) and the metabolic differences among each inhibitor groups were compared using PLS-DA score plots. The observed results suggested that the metabolite changes caused by these two generation of mTOR inhibitors were almost similar and mainly associated with the amino acid, lipid and fatty acid metabolism. In conclusion, further investigations are required to uncover the key differences in the underlying mechanism of these two generations of mTOR inhibitors.
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