Endogenous glutathione adducts.

Endogenous glutathione adducts. Research Abstract Details 

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Endogenous glutathione adducts. Abstract Text:

Ian A Blair,

This review provides an overview of the formation, pharmacology, and toxicology of endogenous glutathione (GSH)-adducts with particular emphasis on GSH-adducts that arise from lipid peroxidation. GSH is the major low-molecular-weight thiol in mammalian cells. It is involved in the formation of endogenous bioactive eicosanoids and is a source of reducing equivalents in a number of biosynthetic reactions. GSH has long been recognized to act as a co-factor in the reduction of reactive oxygen species and lipid hydroperoxides by glutathione peroxidases and glutathione-S-transferases (GSTs). It also plays an important role in the reduction of reactive intermediates derived from arylamines and in the conjugation of reactive intermediates to form S-substituted endogenous GSH-adducts through its nucleophilic cysteine sulfhydryl group. Although some reactive intermediates can form adducts directly, GST-mediated reactions generally predominate. This results in the formation of bioactive endogenous GSH-adducts derived from eicosanoids, isoprostanes, estrogens, catecholamines, and 4-hydroxy-2(E)-nonenal (HNE). Cellular oxidative stress causes increased lipid peroxidation with the concomitant formation of DNA- and protein-reactive bifunctional electrophiles. It has generally been considered that HNE is the most abundant bifunctional electrophile that is formed. Several years ago we discovered that 4-oxo-2(E)-nonenal (ONE) was also a major lipid hydroperoxide-derived bifunctional electrophile. From in vitro studies, we showed that ONE and HNE arose from the common intermediate, 4-hydroperoxy-2(E)-nonenal and also showed that ONE was formed in greater amounts than HNE. We have recently made the unexpected discovery that GSH addition to ONE leads to the formation of an unusual thiadiazabicyclo-ONE-GSH-adduct (TOG), which was characterized as (2S,7R) - 7 - [N - (carboxymethyl)carbamoyl] - 5 - oxo - 12 - pentyl - 9 - thia - 1,6 - diazabicyclo[8.2.1]trideca - 10(13), 11-diene-2-carboxylic acid. TOG is one of the most abundant GSH-adducts formed during peroxide/Fe(II)- or Fe(II)-mediated oxidative stress in EA.hy 926 endothelial cells. As TOG is formed from ONE, these experiments have confirmed that ONE is a major lipid hydroperoxide-derived bifunctional electrophile formed during intracellular oxidative stress. TOG represents the first member of a new class of endogenous GSH-adduct biomarkers that can be used to quantify intracellular oxidative stress. Two other members of the TOG family arise from GST-mediated GSH-adduct formation with dioxododecenoic acid and dioxooctenoic acid, bifunctional electrophiles derived from the carboxy terminus of lipid hydroperoxides. The formation of TOG and TOG-related endogenous GSH-adducts can result from free radical- as well as cyclooxygenase- and lipoxygenase-mediated pathways. Analysis of the GSH-adducts by stable isotope dilution mass spectrometry-based methodology will provide a quantitative measure of enzymatic and non-enzymatic cellular oxidative stress to complement isoprostane measurements. In future studies, it will also be important to establish the biological activity of TOG and its analogs in view of the potent activity of many other endogenous GSH-adducts such as the leukotrienes.

Endogenous glutathione adducts. Publishing Authors By Initials

IA Blair,

For similar animals: chordata: vertebrates: mammals: primates: haplorhini: catarrhini: hominidae: humans research abstracts see: animals: chordata: vertebrates: mammals: primates: haplorhini: catarrhini: hominidae: humans research

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Endogenous glutathione adducts. Journal Published:

PUBLICATION TYPE: Review

Journal: Current drug metabolism

VOLUME: 7

Page Numbers: 853-72

Journal Abbreviation: Curr. Drug Metab.

ISSN: 1389-2002

DAY: 3

MONTH: Dec

YEAR: 2006

Endogenous glutathione adducts. Information

Number of References: 207

LANGUAGE: eng

NlmUniqueID: 100960533

Endogenous glutathione adducts. Keywords Mesh Terms:

KEYWORDS: Humans

MESH TERMS: metabolism

Chemical & Substance for Abstract: Endogenous glutathione adducts. Information

Substance Name: Glutathione

Registry Number: 70-18-8

Grant and Affiliation Information for Endogenous glutathione adducts.

AFFILIATION: Center 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

Country: Netherlands

AGENCY: United States NCRR

GRANT: S10RR019221

ACRONYM: RR

MEDLINETA: Curr Drug Metab

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