Stable isotope-resolved metabolomics and applications for drug development

Teresa W.M. Fan, Pawel K. Lorkiewicz, Katherine Sellers, Hunter N.B. Moseley, Richard M. Higashi, Andrew N. Lane

Research output: Contribution to journalReview articlepeer-review

143 Scopus citations

Abstract

Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response. In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality.

Original languageEnglish
Pages (from-to)366-391
Number of pages26
JournalPharmacology and Therapeutics
Volume133
Issue number3
DOIs
StatePublished - Mar 2012

Bibliographical note

Funding Information:
This work was supported by 1R01CA118434-01A2 , 1RO1CA101199-01 , and 3R01CA118434-02S1 (TWMF), from the National Cancer Institute , the University of Louisville CTSPGP/ARRA grant 20044 , the Kentucky Lung Cancer Research Program OGMB090354B1 and OGMB101380 (TWMF and ANL) and OGMB080120S1 (fellowship to PL), NSF/EPSCoR grant EPS-0447479 (TWMF) for the FT-ICR-MS instrumentation, and the Kentucky Challenge for Excellence . We thank our colleagues for interest and support of stable isotope resolved metabolomics and CREAM.

Keywords

  • Drug discovery
  • Metabolic compartmentation and regulation
  • Metabolomics
  • Pathway reconstruction
  • Stable isotope tracing
  • Systems biochemistry

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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