Journal
TOXICOLOGY IN VITRO
Volume 22, Issue 5, Pages 1198-1204Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2008.03.016
Keywords
proteomics; citalopram; phospholipidosis; human monocytes
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Excessive accumulation of phospholipids leads to phospholipidosis (PL), which disrupts cellular functions, in extreme cases leading to acute or chronic disease. Citalopram and many other cationic amphiphilic drugs (CADs) have been shown to cause PL both in vitro and in vivo. Recent toxicogenomic studies suggest four hypothetical mechanisms for PL (lysosomal enzyme transport decrease, lysosomal phospholipase activity decrease, phospholipids biosynthesis increase or cholesterol biosynthesis increase). However, the post-genomic steps remain largely unknown and proteomic analyses hold significant promise for defining mechanisms of PL induction. In this study U937 monoblastoid cells were exposed to citalopram hydrobromide for 24 h (0, 20, 100 or 200 mu M as citalopram free base) and then harvested for whole cell proteomic analysis using 2-D gel electrophoresis, or transmission electron microscopy (TEM). Protein spots that were significantly altered versus controls were analysed by MALDI-TOF mass spectrometry. Up-regulated proteins were Glyoxalase-1 (Glo 1) and 3-Hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (HMGCS1) in cells with PL shown by TEM (favouring the cholesterol biosynthesis increase hypothesis for citalopram induced PL). Other altered proteins were catalase (up-regulated), beta-actin (up-regulated) and 14-3-3 protein (down-regulated). The function of several of the successfully identified proteins indicates a potential perturbed lipid metabolism. (C) 2008 Elsevier Ltd. All rights reserved.
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