Metabolomic identification of biochemical changes induced by fluoxetine in an insulinoma cell line (MIN6).

Background and purpose: The use of fluoxetine raises the risk of pancreatic beta-cell dysfunction. However, the specific mechanism behind its mechanism of action in beta cells is unknown. This study investigated the cellular response of MIN6 cells to fluoxetine using untargeted cell-based metabolomics. Experimental approach: Metabolic profiling of MIN6 cells was performed using liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Findings/Results: Sixty-six metabolites that had been differentially expressed between the control and fluoxetine-treated groups demonstrated that the citric acid cycle is mainly perturbed by fluoxetine treatment. Conclusion and implications: The current study provides insights into the molecular mechanisms of fluoxetine effects in MIN6 cells.

Exploring the mechanisms of clozapine-induced blood-brain barrier dysfunction using untargeted metabolomics and cellular metabolism analysis.

Brain microvascular endothelial cells (BMVECs) from the blood- brain barrier form a highly selective membrane that protects the brain from circulating blood and maintains a stable microenvironment for the central nervous system. BMVEC dysfunction has been implicated in a variety of neurological and psychiatric disorders. Clozapine, a widely used antipsychotics, has been demonstrated to alter the permeability of BMVECs, but the underlying mechanisms of this effect are not fully understood. In this study, we investigated the effects of clozapine in BMVECs using untargeted metabolomics analysis. Our results illustrated that treatment with clozapine led to significant changes in the metabolic profile of BMVECs, including alterations in amino acid and energy metabolism. These findings suggest that clozapine affects BMVEC permeability through its effects on cellular metabolism. Our study could inform the development of more targeted and effective treatments for understanding the relationships among clozapine, cellular metabolism, and BMVECs in more detail.

Quantification of antipsychotic biotransformation in brain microvascular endothelial cells by using untargeted metabolomics.

Most studies of antipsychotic-therapies have highlighted the discrepancy between plasma and brain pharmacokinetics of antipsychotics, but how the drug changes through the blood brain barrier (BBB) has not been investigated. Cell-based metabolomics using liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis were applied for screening of antipsychotic metabolites in the BBB. We applied this approach to analyze the antipsychotic biotransformation in brain microvascular endothelia cells (BMVECs), the main component of the BBB. From this study, five, four, three, and one metabolite of chlorpromazine, clozapine, haloperidol and risperidone, respectively, were locally metabolized on the BMVECs. These results confirm that there is a drug biotransformation process within the BBB and show that drug metabolite screening employed cell-based metabolomics using LC-MS, combined with multivariate analysis in the study of BMVECs exposed to antipsychotics can provide a way to screen drug metabolites in the BBB.