A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish.

Autor:	Jackstadt MM; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.; Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA., Chamberlain CA; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA., Doonan SR; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA., Shriver LP; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.; Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA., Patti GJ; Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.; Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.; Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63130, USA.; Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2022 Aug 01; Vol. 15 (8). Date of Electronic Publication: 2022 Aug 16.
DOI:	10.1242/dmm.049550
Abstrakt:	An integrated evaluation of the tissue distribution and pharmacodynamic properties of a therapeutic is essential for successful translation to the clinic. To date, however, cost-effective methods to measure these parameters at the systems level in model organisms are lacking. Here, we introduce a multidimensional workflow to evaluate drug activity that combines mass spectrometry-based imaging, absolute drug quantitation across different biological matrices, in vivo isotope tracing and global metabolome analysis in the adult zebrafish. As a proof of concept, we quantitatively determined the whole-body distribution of the anti-rheumatic agent hydroxychloroquine sulfate (HCQ) and measured the systemic metabolic impacts of drug treatment. We found that HCQ distributed to most organs in the adult zebrafish 24 h after addition of the drug to water, with the highest accumulation of both the drug and its metabolites being in the liver, intestine and kidney. Interestingly, HCQ treatment induced organ-specific alterations in metabolism. In the brain, for example, HCQ uniquely elevated pyruvate carboxylase activity to support increased synthesis of the neuronal metabolite, N-acetylaspartate. Taken together, this work validates a multidimensional metabolomics platform for evaluating the mode of action of a drug and its potential off-target effects in the adult zebrafish. This article has an associated First Person interview with the first author of the paper. Competing Interests: Competing interests G.J.P. is a scientific advisory board member for Cambridge Isotope Laboratories and has a collaborative research agreement with Thermo Fisher Scientific. (© 2022. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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