13C Breath Tests in Infections and Beyond

Abstract

Stable isotope labeled compounds are widely used as diagnostic probes in medicine. These diagnostic stable isotope probes are now being expanded in their scope, to provide precise indications of the presence or absence of etiologically significant change in metabolism due to a specific disease. This concept exploits a labeled tracer probe that is a specifically designed substrate of a “gateway” enzyme in a discrete metabolic pathway, whose turnover can be measured by monitoring unidirectional precursor product mass flow. An example of such a probe is the 13C-urea breath test, where labeled urea is given to patients with H. pylori infection. Another example of this kind of probe is used to study the tripeptide glutathione (glu-cys-gly, GSH), which is the most abundant cellular thiol, and protects cells from the toxic effects of reactive oxygen species. Within the gamma glutamyl cycle, 5-oxoproline (L-pyroglutamic acid) is a metabolite generated during GSH catabolism, and is metabolized to glutamic acid by 5-oxoprolinase. This enzyme can also utilize the substrate L-2-oxothiazolidone-4-carboxylate (OTC), to generate intracellular cysteine, which is beneficial to the cell. Thus, labeled (13C) OTC would, under enzymatic attack yield cysteine and 13CO2, and can thus track the state and capacity of glutathione metabolism. Similarly, stable isotope labeled probes can be used to track the activity of the rate of homocysteine clearance, lymphocyte CD26, and liver CYP (cytochrome P450) enzyme activity. In the future, these applications should be able to titrate, in vivo, the characteristics of various specific enzyme systems in the body and their response to stress or infection as well as to treatment regimes.