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Endogenous glutathione adducts.

¹Center for Cancer Pharmacology and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA. ian@spirit.gcrc.upenn.edu

Current Drug Metabolism

|December 16, 2006

Summary

Endogenous glutathione (GSH) adducts, particularly those from lipid peroxidation like the novel thiadiazabicyclo-ONE-GSH-adduct (TOG), serve as biomarkers for oxidative stress. Quantifying these GSH adducts can measure cellular oxidative stress levels.

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Area of Science:

Biochemistry
Cellular Biology
Toxicology

Background:

Glutathione (GSH) is a critical thiol in mammalian cells, involved in antioxidant defense and detoxification.
GSH conjugates with various endogenous reactive intermediates, including those from lipid peroxidation.
Oxidative stress increases lipid peroxidation, generating reactive electrophiles like 4-hydroxy-2(E)-nonenal (HNE) and 4-oxo-2(E)-nonenal (ONE).

Purpose of the Study:

To review the formation, pharmacology, and toxicology of endogenous GSH adducts.
To highlight GSH adducts derived from lipid peroxidation, with a focus on novel adducts.
To establish new biomarkers for quantifying intracellular oxidative stress.

Main Methods:

Literature review on GSH adduct formation and function.
Characterization of the thiadiazabicyclo-ONE-GSH-adduct (TOG) formed from ONE.
Analysis of GSH adducts using stable isotope dilution mass spectrometry.

Main Results:

ONE is a major lipid hydroperoxide-derived electrophile, often formed in greater amounts than HNE.
The novel TOG adduct is a significant GSH adduct formed during oxidative stress in endothelial cells.
TOG and related adducts represent a new class of endogenous biomarkers for oxidative stress.

Conclusions:

TOG and related adducts are reliable biomarkers for quantifying enzymatic and non-enzymatic cellular oxidative stress.
These novel biomarkers complement existing methods like isoprostane measurements.
Further research is needed to elucidate the biological activity of TOG and its analogs.