A novel 4-oxo-2(E)-nonenal-derived endogenous thiadiazabicyclo glutathione adduct formed during cellular oxidative stress

Wenying Jian, Hwa Lee Seon, Clementina Mesaros, Tomoyuki Oe, Maria V. Silva Elipe, Ian A. Blair

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Cellular oxidative stress causes increased lipid peroxidation with the concomitant formation of DNA and protein reactive bifunctional electrophiles. Glutathione (GSH) detoxifies these bifunctional electrophiles by forming GSH adducts. Several years ago we discovered 4-oxo-2(E)-nonenal (ONE) as a major bifunctional electrophile derived from lipid hydroperoxides. We have now made the unexpected discovery that glutafhione-S-transferase (GST)-mediated GSH addition to ONE occurs primarily to C-1 of the α,β-unsaturated ketone rather than to C-3 of the α,β-unsaturated aldehyde. The resulting intermediate rapidly undergoes two intramolecular cyclizations followed by two separate dehydration reactions to provide an unusual thiadiazabicyclo-ONE-GSH adduct (TOG). Quantification of intracellular TOG was performed using stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry after the addition of ONE to cells or as an endogenously derived adduct during peroxide-induced oxidative stress. TOG represents the first member of a new class of thiadiazabicyclo GSH adducts that are formed through GST-mediated addition of GSH to reactive intermediates containing the ONE motif during intracellular oxidative stress. ONE formation can potentially result from free radical pathways as well as cyclooxygenase- and lipoxygenase-mediated pathways. Its aldo-keto reductase-mediated reduction product, 4-oxo-2(E)-nonenol (ONO), was also formed and converted to GSH adducts similar to those formed by 4-hydroxy-2(E)-nonenal (HNE). ONO is isomeric with HNE; therefore, protein and peptide adducts ascribed to arise solely from reactions with endogenous HNE will need to be re-appraised.

Original languageEnglish
Pages (from-to)1008-1018
Number of pages11
JournalChemical Research in Toxicology
Volume20
Issue number7
DOIs
Publication statusPublished - 2007 Jul
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology

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