Metabolic fate of endogenous molecular damage: Urinary glutathione conjugates of DNA-derived base propenals as markers of inflammation
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Jumpathong-2015-Metabolic fate of en.pdf
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Author(s)
Jumpathong, Watthanachai
Chan, Wan
Taghizadeh, Koli
Dedon, Peter C.
Indrakanti, Ramesh Babu
Date Issued
September 2015
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Jumpathong, Watthanachai, Wan Chan, Koli Taghizadeh, I. Ramesh Babu, and Peter C. Dedon. “Metabolic Fate of Endogenous Molecular Damage: Urinary Glutathione Conjugates of DNA-Derived Base Propenals as Markers of Inflammation.” Proc Natl Acad Sci USA 112, no. 35 (August 17, 2015): E4845–E4853.
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Final published version
Abstract
Although mechanistically linked to disease, cellular molecules damaged by endogenous processes have not emerged as significant biomarkers of inflammation and disease risk, due in part to poor understanding of their pharmacokinetic fate from tissue to excretion. Here, we use systematic metabolite profiling to define the fate of a common DNA oxidation product, base propenals, to discover such a biomarker. Based on known chemical reactivity and metabolism in liver cell extracts, 15 candidate metabolites were identified for liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) quantification in urine and bile of rats treated with thymine propenal (Tp). Analysis of urine revealed three metabolites (6% of Tp dose): thymine propenoate and two mercapturate derivatives of glutathione conjugates. Bile contained an additional four metabolites (22% of Tp dose): cysteinylglycine and cysteine derivatives of glutathione adducts. A bis-mercapturate was observed in urine of untreated rats and increased approximately three- to fourfold following CCl[subscript 4]-induced oxidative stress or treatment with the DNA-cleaving antitumor agent, bleomycin. Systematic metabolite profiling thus provides evidence for a metabolized DNA damage product as a candidate biomarker of inflammation and oxidative stress in humans.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1073/pnas.1503945112
