Cadmium-mediated oxidative stress in alveolar epithelial cells induces the expression of gamma-glutamylcysteine synthetase catalytic subunit and glutathione S-transferase alpha and pi isoforms: Potential role of activator protein-1

Exposure of rat alveolar epithelial cells to 10 mu mol/L CdCl2 causes time-dependent increases in steady-state mRNA levels of the gamma -glutamylcysteine synthetase catalytic (heavy) subunit (gamma -GCS) and of glutathione S-transferase isoforms (GST-alpha and GST-pi). The expression of gamma -GCS was significantly increased as early as 2 h after addition of cadmium. Maximal induction of gamma -GCS mRNA (similar to4-fold), at 8 h, was subsequently followed by increases in gamma -GCS activity/protein and glutathione (GSH) levels. Maximal elevations in GST-pi (similar to2-fold) and GST-alpha (similar to 10-fold) transcripts, at 8 and 24 h, respectively, were also accompanied by enhanced GST activity. Cadmium-induced oxidative stress, assessed by alterations in GSH homeostasis and an accelerated rate of intracellular oxidant production, could constitute early events in the signal transduction pathway mediating these responses. The dimeric transcription factor, activator protein-1 (AP-1), may also play a regulatory role in this process. This association is suggested by transcriptional activation of the immediate-early response genes, c-fos and c-jun, within 15 min after exposure to cadmium and by the enhancement of AP-1 DNA binding activity, involving a c-Jun protein complex, which is maximally induced (similar to4-fold) by 2 h. These molecular changes likely function together to protect alveolar epithelial cells against cadmium toxicity.