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

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Abstract
Exposure of rat alveolar epithelial cells to 10 μmol/L CdCl2 causes time-dependent increases in steady-state mRNA levels of the γ-glutamylcysteine synthetase catalytic (heavy) subunit (γ-GCS) and of glutathione S-transferase isoforms (GST-α and GST-π). The expression of γ-GCS was significantly increased as early as 2 h after addition of cadmium. Maximal induction of γ-GCS mRNA (∼4-fold), at 8 h, was subsequently followed by increases in γ-GCS activity/protein and glutathione (GSH) levels. Maximal elevations in GST-π (∼2-fold) and GST-α (∼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 (∼4-fold) by 2 h. These molecular changes likely function together to protect alveolar epithelial cells against cadmium toxicity.

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