Stable isotope-mass spectrometric measurements of molecular fluxes in vivo: emerging applications in drug development.
Therapeutics require not only targets and chemical entities, but tools for measuring actions in vivo. Technologies for evaluating activities, filtering leads and predicting clinical response have lagged behind molecular discovery. 'Systems biology' has not provided systematic methods for predicting metabolic effects in complex systems. The flow of molecules through complex pathways, in contrast, reflects the connectivity relationships and emergent control features of fully assembled networks, but is a quantifiable therapeutic target. This strategy, which combines molecular specificity with intrinsic functional significance, requires different tools. Here, advances in critical pathway flux measurement utilizing stable isotopes and mass spectrometry are described. These include mass isotopomer analysis, heavy-water labeling techniques, secreted probes of intracellular processes, and analytic advances. Several fundamental advantages of kinetic measurements are demonstrated. Measurement of molecular fluxes represents a powerful addition to drug development technology.
Hellerstein
Marc K
MK
University of California at Berkeley, Department of Nutritional Sciences and Toxicology, Berkeley, CA 94720-3104, USA. march@nature.berkeley.edu
Murphy
Elizabeth
E
D000818:Animals; D017666:Deuterium Oxide / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D013058:Mass Spectrometry; D008660:Metabolism / Q000502:physiology*; D008991:Monitoring, Physiologic / Q000379:methods*; D013597:Systems Analysis
D017666:Deuterium Oxide