Stable isotopes, mass spectrometry, and molecular fluxes: applications to toxicology

In order to meet the increasing demands for safe and affordable drugs, improvements in the efficiency and accuracy of every step in drug development are required. Accordingly, new approaches for assessing drug toxicity that are faster and more precise are in demand. Numerous approaches using -omics and systems biology are being developed to meet this demand and, while promising, they have not yet provided the improvements in toxicology promised. Other innovative methodologies for predicting and assessing toxicities should therefore be explored. Here we present a novel approach for directly measuring the in vivo response of specific metabolic pathways to toxic agents. Using stable isotopes and ultra sensitive mass spectrometry, the effect of an agent on myelin synthesis, protein synthesis, or cell proliferation can be directly measured. Examples are presented where this approach is used to detect toxicity in the liver, brain, peripheral neurons, breast, and skin. Collagen synthesis, microglia proliferation, myelin synthesis, tubulin synthesis, hepatic cell proliferation, epidermal cell proliferation and mammary epithelial cell proliferation are quantitatively determined in vivo, in a high throughput manner. This approach avoids the computationally complex approach of systems biology and allows the user to observe the emergent properties of the system directly and quantitatively.