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

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
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Chloroform, suitable for HPLC
Sigma-Aldrich
Chloroform, JIS special grade, ≥99.0%
Sigma-Aldrich
Chloroform, JIS 300, ≥99.0%, for residue analysis
Sigma-Aldrich
Chloroform, SAJ super special grade, ≥99.0%
Sigma-Aldrich
Chloroform, SAJ first grade, ≥99.0%, contains 0.4-0.8% ethanol
Supelco
Metformin hydrochloride solution, 1.0 mg/mL in methanol (as free base), ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Haloperidol solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Chloroform, suitable for HPLC, ≥99.8%, contains 0.5-1.0% ethanol as stabilizer
Sigma-Aldrich
Chloroform, ACS reagent, ≥99.8%, contains 0.5-1.0% ethanol as stabilizer
Sigma-Aldrich
Chloroform, ACS reagent, ≥99.8%, contains amylenes as stabilizer
Sigma-Aldrich
Chloroform, anhydrous, contains amylenes as stabilizer, ≥99%
Sigma-Aldrich
Chloroform, anhydrous, ≥99%, contains 0.5-1.0% ethanol as stabilizer
Sigma-Aldrich
Polysorbate 20
Sigma-Aldrich
Genistein, from Glycine max (soybean), ~98% (HPLC)
Sigma-Aldrich
TWEEN® 20, Low-peroxide; Low-carbonyls
Sigma-Aldrich
TWEEN® 20, Low-peroxide; Low-carbonyls
Sigma-Aldrich
Chloroform, ≥99%, PCR Reagent, contains amylenes as stabilizer
Sigma-Aldrich
TWEEN® 20, BioXtra, viscous liquid
Sigma-Aldrich
TWEEN® 20, viscosity 250-450 mPa.s (25 °C)
Sigma-Aldrich
Haloperidol, powder
Sigma-Aldrich
TWEEN® 20, viscous liquid
Sigma-Aldrich
Genistein, synthetic, ≥98% (HPLC), powder
Sigma-Aldrich
TWEEN® 20, viscous liquid, suitable for cell culture
Sigma-Aldrich
Tetramethylsilane, electronic grade, ≥99.99% trace metals basis
Sigma-Aldrich
Tetramethylsilane, ≥99.0% (GC)
Sigma-Aldrich
8-Octanoyloxypyrene-1,3,6-trisulfonic acid trisodium salt, suitable for fluorescence, ≥90% (HPCE)
Sigma-Aldrich
L-Glutamine, BioUltra, ≥99.5% (NT)
Sigma-Aldrich
Polyoxyethylene (20) sorbitan monolaurate solution, ampule, ~10% in H2O
Sigma-Aldrich
Dimethyl sulfoxide, BioUltra, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
L-Glutamine, meets USP testing specifications, suitable for cell culture, 99.0-101.0%, from non-animal source