INDUCTION OF GAMMA-GLUTAMYLCYSTEINE SYNTHETASE BY CIGARETTE-SMOKE IS ASSOCIATED WITH AP-1 IN HUMAN ALVEOLAR EPITHELIAL-CELLS

Increased levels of glutathione (GSH) occur in the epithelial lining f luid (ELF) of chronic cigarette smokers. Therefore we investigated the effect of cigarette smoke condensate solution (CSC) on GSH synthesis and the regulation of gamma-glutamylcysteine synthetase (gamma GCS) in human type II alveolar epithelial cells (A549). CSC exposure increase d GSH levels, gamma GCS activity and gamma GCS heavy subunit (HS) mRNA , as well as increasing DNA binding of the activator protein-1 (AP-1) and the human antioxidant response element (hARE). Transfection of del etion constructs of the gamma GCS-HS promoter in a chloramphenicol ace tyl transferase (CAT) reporter system revealed that an hARE, present w ithin promoter, is not required for the CSC mediated induction. We con clude that CSC induction of gamma GCS-HS expression is associated with AP-1/AP-1-like responsive elements.