Analysis of an Integrated Human Multiorgan Microphysiological System for Combined Tolcapone Metabolism and Brain Metabolomics

Human-on-a-chip systems are rapidly advancing due to the availability of human stem cells from a variety of tissues, but publications have utilized mostly simple methods of biochemical analysis. Here, we apply mass spectrometry to a sophisticated multiorgan human-on-a-chip system for the comprehensi...

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Bibliographic Details
Main Authors: Wang, Xin (Author), Cirit, Murat (Author), Wishnok, John S. (Author), Griffith, Linda G. (Author), Tannenbaum, Steven R (Author)
Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering (Contributor), Massachusetts Institute of Technology. Department of Chemistry (Contributor)
Format: Article
Language:English
Published: American Chemical Society (ACS), 2020-06-22T13:55:44Z.
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100 1 0 |a Wang, Xin  |e author 
100 1 0 |a Massachusetts Institute of Technology. Department of Biological Engineering  |e contributor 
100 1 0 |a Massachusetts Institute of Technology. Department of Chemistry  |e contributor 
700 1 0 |a Cirit, Murat  |e author 
700 1 0 |a Wishnok, John S.  |e author 
700 1 0 |a Griffith, Linda G.  |e author 
700 1 0 |a Tannenbaum, Steven R  |e author 
245 0 0 |a Analysis of an Integrated Human Multiorgan Microphysiological System for Combined Tolcapone Metabolism and Brain Metabolomics 
260 |b American Chemical Society (ACS),   |c 2020-06-22T13:55:44Z. 
856 |z Get fulltext  |u https://hdl.handle.net/1721.1/125910 
520 |a Human-on-a-chip systems are rapidly advancing due to the availability of human stem cells from a variety of tissues, but publications have utilized mostly simple methods of biochemical analysis. Here, we apply mass spectrometry to a sophisticated multiorgan human-on-a-chip system for the comprehensive study of tolcapone metabolite profiling and metabolomics. The developed human-on-a-chip includes seven interacting microphysiological systems (MPSs), brain, pancreas, liver, lung, heart, gut, and endometrium, with a mixer chamber for systemic circulation and tolcapone dose. We investigated tolcapone metabolism by analyzing the circulating medium using mass spectrometry. Twelve tolcapone metabolites were identified, three of which are newly reported. These metabolites demonstrated that oxidation, reduction, and conjugation reactions were the most important routes of tolcapone metabolism. In parallel, metabolomics in brain MPS evaluated the tolcapone influences on endogenous pathways in human brain. Untargeted metabolomics identified 18 key biomarkers significantly changed in human brain MPS after tolcapone dosing, which were mainly associated with perturbation of tryptophan and phenylalanine metabolism (BH4 cycle), glycerophospholipid metabolism, energy metabolism, and aspartate metabolism. This is the first example of successfully combining drug metabolism, metabolomics, and cell engineering to capture complex human physiology and the multiorgan interactions; the results we present here could be a step toward using analytical chemistry to advance the utilization of human-on-a-chip for testing both drug efficacy and toxicity in a single system. 
520 |a U.S. Army Research Office & the Defense Advanced Research Project Agency (Cooperative Agreement no. W911NF-12-2-0039) 
546 |a en 
655 7 |a Article 
773 |t Analytical Chemistry