Crystalline silica is well-known to induce oxidative stress as a consequence of both surface-derived generation of free radicals and intracellular production of reactive oxygen species upon phagocytosis; the mechanism of the latter is still partially unknown. In this study, we report that in murine alveolar MH-S macrophages, a 24 h incubation with quartz particles (80 microg/cm(2)) inhibits the glucose 6-phosphate dehydrogenase (G6PD) (1) activity by 70% and the pentose phosphate pathway by 30%. Such effects are accompanied by a 50% decrease of intracellular glutathione, a 35% increase of thiobarbituric acid reactive products (index of lipoperoxidation), and a 5-fold increase of leakage of lactate dehydrogenase in the extracellular medium (index of cytotoxicity). Quartz inhibits G6PD but not other oxidoreductases, and such inhibition is fully prevented by glutathione, suggesting that silica exerts on G6PD an oxidative damage. Our data provide a new additional mechanism by which silica may induce oxidative stress, that is, by inhibiting the pentose phosphate pathway, one of the main antioxidant metabolic pathways of the cell.