Abstract:
:High content omic techniques in combination with stable human in vitro cell culture systems have the potential to improve on current pre-clinical safety regimes by providing detailed mechanistic information of altered cellular processes. Here we investigated the added benefit of integrating transcriptomics, proteomics and metabolomics together with pharmacokinetics for drug testing regimes. Cultured human renal epithelial cells (RPTEC/TERT1) were exposed to the nephrotoxin Cyclosporine A (CsA) at therapeutic and supratherapeutic concentrations for 14days. CsA was quantified in supernatants and cellular lysates by LC-MS/MS for kinetic modeling. There was a rapid cellular uptake and accumulation of CsA, with a non-linear relationship between intracellular and applied concentrations. CsA at 15μM induced mitochondrial disturbances and activation of the Nrf2-oxidative-damage and the unfolded protein-response pathways. All three omic streams provided complementary information, especially pertaining to Nrf2 and ATF4 activation. No stress induction was detected with 5μM CsA; however, both concentrations resulted in a maximal secretion of cyclophilin B. The study demonstrates for the first time that CsA-induced stress is not directly linked to its primary pharmacology. In addition we demonstrate the power of integrated omics for the elucidation of signaling cascades brought about by compound induced cell stress.
journal_name
J Proteomicsjournal_title
Journal of proteomicsauthors
Wilmes A,Limonciel A,Aschauer L,Moenks K,Bielow C,Leonard MO,Hamon J,Carpi D,Ruzek S,Handler A,Schmal O,Herrgen K,Bellwon P,Burek C,Truisi GL,Hewitt P,Di Consiglio E,Testai E,Blaauboer BJ,Guillou C,Huber CG,Lukadoi
10.1016/j.jprot.2012.11.022subject
Has Abstractpub_date
2013-02-21 00:00:00pages
180-94eissn
1874-3919issn
1876-7737pii
S1874-3919(12)00777-4journal_volume
79pub_type
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journal_title:Journal of proteomics
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pub_type: 杂志文章,多中心研究,随机对照试验
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