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Gamma-glutamyldehydroalanylglycine is an electrophilic metabolite of glutathione.

Authors
Peer-CJ; Younis-IR; Bukowski-VC; Leonard-SS; Petros-WP; Callery-PS
Source
Drug Metab Rev 2009 Oct; 41(Suppl 3):129-130
NIOSHTIC No.
20037713
Abstract
Gamma-Glutamyldehydroalanylglycine (EdAG) is a dethiolated, electrophilic metabolite of glutathione (GSH) derived from the Phase II conjugation of GSH with busulfan catalyzed by glutathione S-transferase (GST), specifically isoform A1-1. Electrophilic substrates of GST, such as ethacrynic acid and 1-chloro-2,4-dinitrobenzene, have been shown to be irreversible inhibitors of glutathione transferase activity at high concentrations in vitro. EdAG at high concentration (10 mM) was found to be an irreversible inhibitor of human GSTA1-1, and at lower concentrations showed noncompetitive inhibition (Ki = 11 microM). Conversion of GSH to EdAG represents a loss of thiol-related redox properties and the gain of a dehydroalanine group with the potential to scavenge ROS. EdAG competed with DMPO for hydroxyl radical generated in the Fenton reaction in a concentration-dependent manner. The results suggest a stabilized carbon-based captodative radical intermediate in the reaction of EdAG with hydroxyl radical. In support of a captodative mechanism was the identification of a dimerized gamma-glutamylserylglycine as a product in the reaction of hydroxyl radical with EdAG. In summary, it was determined here that EdAG can inhibit GSTA1-1 and also scavenge hydroxyl radical in vitro through a proposed captodative mechanism. The results indicate that the chemical instability of a busulfan metabolite results in the conversion of GSH into EdAG, a reactive compound that is a Michael acceptor and free radical scavenger. The biological implications of EdAG reactivity may have an impact on GSH biochemistry, cellular free radical reactivity, and busulfan toxicology.
Keywords
Chemical-analysis; Chemical-binding; Chemical-composition; Chemical-hypersensitivity; Chemical-indicators; Chemical-reactions; Chemical-structure; Chemical-synthesis; Biochemical-analysis; Biochemical-indicators; Toxic-effects
CODEN
DMTRAR
CAS No.
70-18-8; 55-98-1
Publication Date
20091001
Document Type
Abstract
Fiscal Year
2010
NTIS Accession No.
NTIS Price
ISSN
0360-2532
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Drug Metabolism Reviews
State
WV
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