title: Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis.
abstract: 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.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Zielinski
authors.affiliation: 1] Cancer Research Center, Sanford-Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2] UC Merced, Quantitative and Systems Biology, University of California Merced, 5200 North Lake Road, Merced, California 95343, USA.
authors.forename: Fabian V
authors.identifier: 0000000198895727
authors.initials: FV
authors.lastname: Filipp
authors.affiliation: 1] Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, USA [2] Sinopia Biosciences, 600 W Broadway Suite 700, San Diego, CA 92101, USA.
authors.forename: Aarash
authors.initials: A
authors.lastname: Bordbar
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, Building 208, Lyngby DK-2800, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Cancer Research Center, Sanford-Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: 1] Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, USA [2] Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kogle Alle 6, Horshølm 2970, Denmark.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Herrgard
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Mo
authors.affiliation: 1] Department of Bioengineering, University of California, San Diego, La Jolla, California 92093-0412, USA [2] Department of Pediatrics, University of California, San Diego, La Jolla, California 92093-0412, USA.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
mesh_terms: D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D010597:Pharmacogenetics