Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption

Tomoyoshi Soga, Richard Baran, Makoto Suematsu, Yuki Ueno, Satsuki Ikeda, Tadayuki Sakurakawa, Yuji Kakazu, Takamasa Ishikawa, Martin Robert, Takaaki Nishioka, Masaru Tomita

Research output: Contribution to journalArticle

442 Citations (Scopus)

Abstract

Metabolomics is an emerging tool that can be used to gain insights into cellular and physiological responses. Here we present a metabolome differential display method based on capillary electrophoresis time-of-flight mass spectrometry to profile liver metabolites following acetaminophen-induced hepatotoxicity. 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 γ-glutamylcysteine and glutathione synthetase. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption. Overall, our results provide a broad picture of hepatic metabolite changes following acetaminophen treatment. In addition, we specifically found that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. Ourmethod can thus pinpoint specific metabolite changes and provide insights into the perturbation of metabolic pathways on a large scale and serve as a powerful new tool for discovering low molecular weight biomarkers.

Original languageEnglish
Pages (from-to)16768-16776
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number24
DOIs
Publication statusPublished - 2006 Jun 16

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Soga, T., Baran, R., Suematsu, M., Ueno, Y., Ikeda, S., Sakurakawa, T., Kakazu, Y., Ishikawa, T., Robert, M., Nishioka, T., & Tomita, M. (2006). Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption. Journal of Biological Chemistry, 281(24), 16768-16776. https://doi.org/10.1074/jbc.M601876200