AbstractThe oxidative stress could have a dual action on glutathione S‐transferase (GST) P1‐1 metabolism: transcriptional induction and/or polymerization. The former should represent a form of adaptation to oxidative stress and contribute to protect the cell, the latter one should activate apoptosis via c‐Jun N‐terminal kinase (JNK). We studied the effect of etoposide on human neuroblastoma cell line SH‐SY5Y and on an etoposide‐resistant clone to investigate whether a pleiotropic effect of etoposide on the redox status of the cell exists which is able to interfere with apoptosis through the GST P1‐1 system. Etoposide treatment was able to induce GST P1‐1 polymerization and activation of apoptosis. The data obtained from our etoposide‐resistant clone and the possibility to reverse the sensitive phenotype to a resistant one by means of hexyl‐glutathione preincubation, seem to suggest that cellular levels of glutathione have a key role in protecting GST P1‐1 by oxidation and consequently the cell's decision between life and death. J. Cell. Biochem. 86: 340–347, 2002. © 2002 Wiley‐Liss, Inc.