Saltar al contenido
Merck

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

Nature communications (2015-06-10)
Daniel C Zielinski, Fabian V Filipp, Aarash Bordbar, Kasper Jensen, Jeffrey W Smith, Markus J Herrgard, Monica L Mo, Bernhard O Palsson
RESUMEN

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.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Dimetilsulfóxido, Hybri-Max, sterile-filtered, BioReagent, suitable for hybridoma, ≥99.7%
Sigma-Aldrich
Dimetilsulfóxido, for molecular biology
Sigma-Aldrich
Dimetilsulfóxido, sterile-filtered, BioPerformance Certified, meets EP, USP testing specifications, suitable for hybridoma
Sigma-Aldrich
Dimetilsulfóxido, ≥99.5% (GC), suitable for plant cell culture
Sigma-Aldrich
Dimetilsulfóxido, anhydrous, ≥99.9%
Sigma-Aldrich
TWEEN® 20, viscous liquid
Sigma-Aldrich
L-Glutamina, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source
Sigma-Aldrich
TWEEN® 20, viscous liquid, suitable for cell culture
Sigma-Aldrich
L-Glutamina
Sigma-Aldrich
TWEEN® 20, BioXtra, viscous liquid
Sigma-Aldrich
Dimetilsulfóxido, BioUltra, for molecular biology, ≥99.5% (GC)
SAFC
L-Glutamina
Sigma-Aldrich
Cloroformo, anhydrous, ≥99%, contains 0.5-1.0% ethanol as stabilizer
Sigma-Aldrich
Genistein, synthetic, ≥98% (HPLC), powder
Sigma-Aldrich
Polysorbate 20
Sigma-Aldrich
Pyridoxine, ≥98%
Sigma-Aldrich
Dimetilsulfóxido, PCR Reagent
Sigma-Aldrich
TWEEN® 20, viscosity 250-450 mPa.s (25 °C)
Sigma-Aldrich
Cloroformo, anhydrous, contains amylenes as stabilizer, ≥99%
Sigma-Aldrich
Dimetilsulfóxido, meets EP testing specifications, meets USP testing specifications
Sigma-Aldrich
L-Glutamina, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
Tetramethylsilane, ≥99.0% (GC)
Sigma-Aldrich
L-Carnitine inner salt, synthetic, ≥98%
Sigma-Aldrich
Cloroformo, JIS special grade, ≥99.0%
Sigma-Aldrich
Polyoxyethylene (20) sorbitan monolaurate solution, ampule, ~10% in H2O
Sigma-Aldrich
Haloperidol, powder
Sigma-Aldrich
Cloroformo, ≥99%, PCR Reagent, contains amylenes as stabilizer
Sigma-Aldrich
L-Glutamina, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
L-Glutamina
Sigma-Aldrich
TWEEN® 20, Low-peroxide; Low-carbonyls