メタボローム解析によるバイオマーカーの探索

抄録

Metabolomics has become a powerful new tool for gaining insights into cellular and physiological responses (1,2). Here we have developed a comprehensive and quantitative analysis method based on capillary electrophoresis mass spectrometry (CE-TOFMS). Metabolites are first separated by CE based on their charge and size and then selectively detected at their exact mass molecular ions by TOFMS detector (3). We applied the CE-TOFMS to profile liver metabolites following acetaminophen- induced hepatotoxicity and revealed ophthalmate as a sensitive indicator of reduced glutathione (GSH) depletion. We globally detected 1,859 peaks in mouse liver extracts, and highlighted multiple changes in metabolite levels, including an activation of the ophthalmate biosynthesis pathway. We confirmed that ophthalmate was synthesized from 2-aminobutyrate through consecutive reactions with g-glutamylcysteine and glutathione synthetase like GSH. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption (3). Our results specifically indicate that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. We also applied this approach to quantify hundreds metabolites in human colon and stomach tumor and normal tissues (4). The results highlight tumor-specific metabolic features characteristic of the Warburg effect and active amino acid uptake in both tumor types together with organ-specific differences presumably linked to oxygen availability. The findings demonstrate the potential of CE-TOFMS-based metabolomics for cancer research and suggest avenues for the development of novel anticancer therapeutics that target tumor-specific metabolism. References 1. Soga, T., et al., J. Proteome Res. 2.　488-494, 2003. 2. Ishii, N., Soga, T., et al., Science 316, 593-597, 2007. 3. Soga, T., et al., J. Biol. Chem. 281, 16768,-16776 2006. 4. Hirayama, A., et al. Cancer Res. in press.