A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish
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 mu...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-08-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/15/8/dmm049550 |
| _version_ | 1828331159887544320 |
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| author | Madelyn M. Jackstadt Casey A. Chamberlain Steven R. Doonan Leah P. Shriver Gary J. Patti |
| author_facet | Madelyn M. Jackstadt Casey A. Chamberlain Steven R. Doonan Leah P. Shriver Gary J. Patti |
| author_sort | Madelyn M. Jackstadt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T20:49:01Z |
| format | Article |
| id | doaj.art-4c20179e5bb64a0699c5531d951d7e9a |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-13T20:49:01Z |
| publishDate | 2022-08-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-4c20179e5bb64a0699c5531d951d7e9a2022-12-22T02:30:35ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-08-0115810.1242/dmm.049550049550A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafishMadelyn M. Jackstadt0Casey A. Chamberlain1Steven R. Doonan2Leah P. Shriver3Gary J. Patti4 Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA 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.http://dmm.biologists.org/content/15/8/dmm049550zebrafishmetabolomicspharmacodynamicsmass spectrometry imagingdrug discovery |
| spellingShingle | Madelyn M. Jackstadt Casey A. Chamberlain Steven R. Doonan Leah P. Shriver Gary J. Patti A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish Disease Models & Mechanisms zebrafish metabolomics pharmacodynamics mass spectrometry imaging drug discovery |
| title | A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish |
| title_full | A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish |
| title_fullStr | A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish |
| title_full_unstemmed | A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish |
| title_short | A multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish |
| title_sort | multidimensional metabolomics workflow to image biodistribution and evaluate pharmacodynamics in adult zebrafish |
| topic | zebrafish metabolomics pharmacodynamics mass spectrometry imaging drug discovery |
| url | http://dmm.biologists.org/content/15/8/dmm049550 |
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