THE CELL-SPECIFIC ANTIPROLIFERATIVE EFFECT OF REDUCED GLUTATHIONE IS MEDIATED BY GAMMA-GLUTAMYL TRANSPEPTIDASE-DEPENDENT EXTRACELLULAR PROOXIDANT REACTIONS

We have shown earlier that extracellular GSH can exert a cell-specific growth-inhibitory effect on human turner cells. In the present study, 2 human ovarian carcinoma cell lines (A2780 and IGROV-I) were used to investigate the biochemical basis of the GSH growth-inhibitory effect , Whereas cells were resistant, A2780 cells were sensitive to a I hr e xposure to GSH, as assessed by the growth inhibition assay. Analysis o f relevant GSH-dependent enzymes indicated that A2780 cells had low le vel of GSH S-transferase, glutathione reductase and gamma-glutamyl tra nspeptidase (gamma-GT) activities in comparison with those of IGROV-I cells, and GSH peroxidase activity was undetectable in A2780 cells, Th e GSH effect was reversed by catalase and by dithiothreitol, indicatin g the occurrence of oxidative phenomena resulting in the impairment of critical cellular thiols, Indeed treatment of cells with H2O2 also re sulted in growth inhibition, which was more marked in A2780 cells, The gamma-glutamyl acceptor glycylglycine, a cosubstrate for gamma-GT, po tentiated the growth-inhibitory effect of GSM, which in contrast was d ecreased by the gamma-GT inhibitors, serine-borate complex and acivici n, suggesting that the production of reactive forms of oxygen (probabl y H2O2) was mediated by cysteinyl-glycine after GSH hydrolysis, The re sults support that the growth-inhibitory effect of low GSH concentrati on is the result of oxidative damage related to extracellular GSH meta bolism. (C) 1997 Wiley-Liss, Inc.