Abstract:
:The mechanisms involved in the cytotoxicity of 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone, a model compound for hydroquinone derived mercapturic acids, were investigated in rat renal proximal tubule cells. 2-Bromo-3-(N-acetylcystein-S-yl)hydroquinone induced a time- and concentration-dependent decrease in cell viability and in the levels of cellular glutathione. Antioxidants such as N,N'-diphenyl-p-phenylene diamine and ascorbic acid and the iron chelator desferrioxamine very efficiently protected the cells from 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone without influencing glutathione depletion. The acetoxymethyl ester of the Ca2+ chelator Quin-2, the inhibitor of the Ca(2+)- and Mg(2+)-dependent endonucleases, aurintricarboxylic acid and the poly(ADP-ribose)-polymerase inhibitor 3-aminobenzamide also ameliorated 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone cytotoxicity. Moreover, 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone depleted Ca2+ from isolated kidney mitochondria, increased the amount of malondialdehyde in rat kidney cells and induced DNA double-strand breaks in renal cells in culture. These results suggest that renal cells oxidize 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone to the corresponding quinone; this soft electrophile reacts rapidly with glutathione, thus depleting cellular glutathione concentrations as indicated by the tentative identification of a 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone thioether in the incubation medium of renal cells treated with the mercapturate. As a result of the massive glutathione depletion, peroxidative mechanisms then cause an elevation of the cytosolic concentrations of ionized calcium; impairment of the ability of the mitochondria to sequester Ca2+ plays an important role in the elevation of the Ca2+ concentration. Finally, activation of Ca(2+)- and Mg(2+)-dependent endonucleases results in DNA damage and cell death.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Vamvakas S,Bittner D,Koob M,Glück S,Dekant Wdoi
10.1016/0009-2797(92)90045-msubject
Has Abstractpub_date
1992-08-14 00:00:00pages
183-99issue
2eissn
0009-2797issn
1872-7786pii
0009-2797(92)90045-Mjournal_volume
83pub_type
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