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Am J Physiol Endocrinol Metab 297: E260-E269, 2009. First published April 28, 2009; doi:10.1152/ajpendo.00080.2009
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TRANSLATIONAL PHYSIOLOGY

Dynamics of glutathione and ophthalmate traced with 2H-enriched body water in rats and humans

Rajan S. Kombu,1 Guo-Fang Zhang,1 Rime Abbas,2 John J. Mieyal,3 Vernon E. Anderson,4 Joanne K. Kelleher,5 Juan R. Sanabria,2 and Henri Brunengraber1

Departments of 1Nutrition, 2Surgery, 3Pharmacology, and 4Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio; and 5Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts

Submitted 10 February 2009 ; accepted in final form 24 April 2009

We developed a LC-MS-MS assay of the 2H labeling of free glutathione (GSH) and bound glutathione [GSSR; which includes all DTT-reducible forms, primarily glutathione disulfide (GSSG) and mixed disulfides with proteins] and ophthalmate (an index of GSH depletion) labeled from 2H-enriched body water. In rats whose body water was 2.5% 2H enriched for up to 31 days, GSH labeling follows a complex pattern because of different rates of labeling of its constitutive amino acids. In rats infused with [13C2,15N-glycine]glutathione, the rate of appearance of plasma GSH was 2.1 µmol·min–1·kg–1, and the half-life of plasma GSH/GSSR was 6–8 min. In healthy humans whose body fluids were 0.5% 2H enriched, the 2H labeling of GSH/GSSR and ophthalmate can be precisely measured after 4 h, with GSH being more rapidly labeled than GSSR. Since plasma GSH/GSSR derives mostly from liver, this technique opens the way to 2) probe noninvasively the labeling pattern and redox status of the liver GSH system in humans and 2) assess the usefulness of ophthalmate as an index of GSH depletion.

mass isotopomer analysis; oxidative stress; protein synthesis; peptide synthesis; deuterated water; liver


Address for reprint requests and other correspondence: H. Brunengraber, Dept. of Nutrition, Case Western Reserve University, School of Medicine, 10900 Euclid Ave., W-G48, Cleveland, OH 44106-4954 (e-mail: hxb8{at}case.edu)






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