CELLULAR MECHANISMS OF RESISTANCE TO CHRONIC OXIDATIVE STRESS

Oxidative stress is implicated in several pathologies such as AIDS, Al zheimer's disease, and Parkinson's disease, as well as in normal aging . As a model system to study the response of cells to oxidative insult s, glutamate toxicity on a mouse nerve cell line, HT-22, was examined. Glutamate exposure kills HT-22 via a nonreceptor-mediated oxidative p athway by blocking cystine uptake and causing depletion of intracellul ar glutathione (GSH), leading to the accumulation of reactive oxygen s pecies and, ultimately, apoptotic cell death. Several HT-22 subclones that are 10-fold resistant to exogenous glutamate were isolated and th e mechanisms involved in resistance characterized. The expression leve ls of neither heat shock proteins nor apoptosis-related proteins are c hanged in the resistant cells. In contrast, the antioxidant enzyme cat alase, but not glutathione peroxidase nor superoxide dismutase, is mor e highly expressed in the resistant than in the parental cells. In add ition, the resistant cells have enhanced rates of GSH regeneration due to higher activities of the GSH metabolic enzymes gamma-glutamylcyste ine synthetase and GSH reductase, and GSH S-transferases activities ar e also elevated. As a consequence of these alterations, the glutamate resistant cells are also more resistant to organic hydroperoxides and anticancer drugs that affect these GSH enzymes. These results indicate that resistance to apoptotic oxidative stress may be acquired by coor dinated changes in multiple antioxidant pathways. (C) 1998 Elsevier Sc ience Inc.