Global metabolomics approach in in vitro and in vivo models reveals hepatic glutathione depletion induced by amorphous silica nanoparticles

The present study aimed to investigate the mechanisms involved in amorphous silica nanoparticles (aSiNPs)-mediated hepatotoxicity through the evaluation of changes in global metabolomics in in vitro and in vivo systems. H-1 NMR-based non-targeted global metabolomics and biochemical approaches were conducted in an aSiNPs-treated human hepatoma cell line (HepG2) and in ICR mice liver. The non-targeted NMR-based metabolomic analysis, followed by pathway analysis, revealed the perturbation of glutathione metabolism and the depletion of the glutathione pool after aSiNPs treatment in both in vitro (HepG2 cells) and in vivo systems. The total glutathione level, glutathione-S-transferase enzyme activity, and antioxidant gene expression strongly corroborated the metabolomic analysis results. The in vitro results were further supported by the in vivo data, specifically for metabolites profiling (Pearson Correlation coefficient is 0.462 (p=0.026)). Furthermore, the depletion of glutathione, the formation of NADPH oxidase-mediated reactive oxygen species, and oxidative stress were evident in aSiNPs-treated HepG2 cells. Overall, the suppression of glutathione metabolism and oxidative stress are among the principal causes of aSiNPs-mediated hepatotoxicity.