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J. Biol. Chem., Vol. 281, Issue 24, 16768-16776, June 16, 2006

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Differential Metabolomics Reveals Ophthalmic Acid as an Oxidative Stress Biomarker Indicating Hepatic Glutathione Consumption^*

Tomoyoshi Soga¹², Richard Baran¹, Makoto Suematsu^¶13, Yuki Ueno, Satsuki Ikeda, Tadayuki Sakurakawa^¶, Yuji Kakazu, Takamasa Ishikawa, Martin Robert, Takaaki Nishioka, and Masaru Tomita

From the Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan, Human Metabolome Technologies Inc., Tsuruoka, Yamagata 997-0017, Japan, and the ^¶Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

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 -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.

Received for publication, February 27, 2006 , and in revised form, March 29, 2006.

^* This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) (the 21st Century COE Program entitled "Understanding and Control of Life's Function via Systems Biology," and a grant from Grant-in-aid of Creative Researches and Leading Project for Biosimulation from MEXT in Japan as well as research funds from Yamagata prefectural government and Tsuruoka city. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0017, Japan. Tel.: 81-235-29-0528; Fax: 81-0235-29-0530; E-mail: soga{at}sfc.keio.ac.jp. ³ To whom correspondence may be addressed: Dept. of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: msuem{at}sc.itc.keio.ac.jp.

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