Noninvasive in vivo magnetic resonance measures of glutathione synthesis in human and rat liver as an oxidative stress biomarker

Authors

  • John T. Skamarauskas,

    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Newcastle Magnetic Resonance Center, Newcastle University, Newcastle upon Tyne, UK
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  • Fiona Oakley,

    1. Newcastle Magnetic Resonance Center, Newcastle University, Newcastle upon Tyne, UK
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  • Fiona E. Smith,

    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Newcastle Magnetic Resonance Center, Newcastle University, Newcastle upon Tyne, UK
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  • Carlo Bawn,

    1. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
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  • Michael Dunn,

    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Medical Toxicology Center, Newcastle University, Newcastle upon Tyne, UK
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  • Daniel S. Vidler,

    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Medical Toxicology Center, Newcastle University, Newcastle upon Tyne, UK
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  • Matthew Clemence,

    1. Philips Healthcare Clinical Science, Guildford, UK
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  • Peter G. Blain,

    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Medical Toxicology Center, Newcastle University, Newcastle upon Tyne, UK
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  • Roy Taylor,

    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Newcastle Magnetic Resonance Center, Newcastle University, Newcastle upon Tyne, UK
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  • Michael P. Gamcsik,

    1. Joint Department of Biomedical Engineering, University of North Carolina, Chapel Hill and North Carolina State University, Raleigh, NC
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    • Michael P. Gamcsik and Peter E. Thelwall are joint senior authors.

  • Peter E. Thelwall

    Corresponding author
    1. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    2. Newcastle Magnetic Resonance Center, Newcastle University, Newcastle upon Tyne, UK
    • Address reprint requests to: Peter E Thelwall, Ph.D., Newcastle Magnetic Resonance Center, Campus for Aging and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK. E-mail: pete.thelwall@ncl.ac.uk; fax: +44 (0) 191 208 1151.

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    • Michael P. Gamcsik and Peter E. Thelwall are joint senior authors.


  • See Editorial on Page 2077

  • Potential conflict of interest: M.C. is a full-time employee of Philips Healthcare.

  • This work was supported by grant G0801239 from the Medical Research Council, UK (to P.E.T.) and by grant R01CA114365 from the National Institutes of Health (to M.P.G.).

Abstract

Oxidative stress (OS) plays a central role in the progression of liver disease and in damage to liver by toxic xenobiotics. We have developed methods for noninvasive assessment of hepatic OS defenses by measuring flux through the glutathione (GSH) synthesis pathway. 13C-labeled GSH is endogenously produced and detected by in vivo magnetic resonance after administration of [2-13C]-glycine. We report on a successful first-ever human demonstration of this approach as well as preclinical studies demonstrating perturbed GSH metabolism in models of acute and chronic OS. Human studies employed oral administration of [2-13C]-glycine and 13C spectroscopy on a 3T clinical magnetic resonance (MR) imaging scanner and demonstrated detection and quantification of endogenously produced 13C-GSH after labeled glycine ingestion. Plasma analysis demonstrated that glycine 13C fractional enrichment achieved steady state during the 6-hour ingestion period. Mean rate of synthesis of hepatic 13C-labeled GSH was 0.32 ± 0.18 mmole/kg/hour. Preclinical models of acute OS and nonalcoholic steatohepatitis (NASH) comprised CCl4-treated and high-fat, high-carbohydrate diet-fed Sprague-Dawley rats, respectively, using intravenous administration of [2-13C]-glycine and observation of 13C-label metabolism on a 7T preclinical MR system. Preclinical studies demonstrated a 54% elevation of GSH content and a 31% increase in flux through the GSH synthesis pathway at 12 hours after acute insult caused by CCl4 administration, as well as a 23% decrease in GSH content and evidence of early steatohepatitis in the model of NASH. Conclusion: Our data demonstrate in vivo 13C-labeling and detection of GSH as a biomarker of tissue OS defenses, detecting chronic and acute OS insults. The methods are applicable to clinical research studies of hepatic OS in disease states over time as well as monitoring effects of therapeutic interventions. (Hepatology 2014;59:2321–2330)

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