Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption.
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 gamma-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. Our method 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.
Soga
Tomoyoshi
T
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan. soga@sfc.keio.ac.jp
Baran
Richard
R
Suematsu
Makoto
M
Ueno
Yuki
Y
Ikeda
Satsuki
S
Sakurakawa
Tadayuki
T
Kakazu
Yuji
Y
Ishikawa
Takamasa
T
Robert
Martin
M
Nishioka
Takaaki
T
Tomita
Masaru
M
D000818:Animals; D004151:Dipeptides / Q000378:metabolism; D019075:Electrophoresis, Capillary; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism*; D005981:Glutathione Synthase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009842:Oligopeptides / Q000378:metabolism*; D018384:Oxidative Stress
D004151:Dipeptides; D009842:Oligopeptides; C016632:ophthalmic acid; D005981:Glutathione Synthase; D005978:Glutathione; C017341:gamma-glutamylcysteine