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Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...

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Autores principales: Zielinski, Daniel C., Filipp, Fabian V., Bordbar, Aarash, Jensen, Kasper, Smith, Jeffrey W., Herrgard, Markus J., Mo, Monica L., Palsson, Bernhard O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Pub. Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468904/
https://www.ncbi.nlm.nih.gov/pubmed/26055627
http://dx.doi.org/10.1038/ncomms8101
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author Zielinski, Daniel C.
Filipp, Fabian V.
Bordbar, Aarash
Jensen, Kasper
Smith, Jeffrey W.
Herrgard, Markus J.
Mo, Monica L.
Palsson, Bernhard O.
author_facet Zielinski, Daniel C.
Filipp, Fabian V.
Bordbar, Aarash
Jensen, Kasper
Smith, Jeffrey W.
Herrgard, Markus J.
Mo, Monica L.
Palsson, Bernhard O.
author_sort Zielinski, Daniel C.
collection PubMed
description Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways dysregulated by drugs are linked to the development of side effects. We show such dysregulated metabolic pathways contain genes with sequence variants affecting side effect incidence, play established roles in pathophysiology, have significantly altered activity in corresponding diseases, are susceptible to metabolic inhibitors and are effective targets for therapeutic nutrient supplementation. Our results indicate that metabolic dysregulation represents a common mechanism underlying side effect pathogenesis that is distinct from the role of metabolism in drug clearance. We suggest that elucidating the relationships between the cellular response to drugs, genetic variation of patients and cell metabolism may help managing side effects by personalizing drug prescriptions and nutritional intervention strategies.
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spelling pubmed-44689042015-06-30 Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis Zielinski, Daniel C. Filipp, Fabian V. Bordbar, Aarash Jensen, Kasper Smith, Jeffrey W. Herrgard, Markus J. Mo, Monica L. Palsson, Bernhard O. Nat Commun Article Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways dysregulated by drugs are linked to the development of side effects. We show such dysregulated metabolic pathways contain genes with sequence variants affecting side effect incidence, play established roles in pathophysiology, have significantly altered activity in corresponding diseases, are susceptible to metabolic inhibitors and are effective targets for therapeutic nutrient supplementation. Our results indicate that metabolic dysregulation represents a common mechanism underlying side effect pathogenesis that is distinct from the role of metabolism in drug clearance. We suggest that elucidating the relationships between the cellular response to drugs, genetic variation of patients and cell metabolism may help managing side effects by personalizing drug prescriptions and nutritional intervention strategies. Nature Pub. Group 2015-06-09 /pmc/articles/PMC4468904/ /pubmed/26055627 http://dx.doi.org/10.1038/ncomms8101 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Zielinski, Daniel C.
Filipp, Fabian V.
Bordbar, Aarash
Jensen, Kasper
Smith, Jeffrey W.
Herrgard, Markus J.
Mo, Monica L.
Palsson, Bernhard O.
Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
title Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
title_full Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
title_fullStr Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
title_full_unstemmed Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
title_short Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
title_sort pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468904/
https://www.ncbi.nlm.nih.gov/pubmed/26055627
http://dx.doi.org/10.1038/ncomms8101
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