During acute pancreatitis there is marked depletion of glutathione in páncreas. The rapid restoration of glutathione levels may be critical for the evolution towards a mild form of the disease. Aims: 1) To determine the protein and mRNA expression of gamma-glutamyl cysteine synthetase in páncreas in necrotizing and edematous pancreatitits; 2) To assess the recruitment of transcription factors and RNA polymerase II to the promotor regions of GCS and the role of cytosolic ribonuclease activity.

Methods: Taurocholate-induced (necrotizing) and caerulein-induced (edematous) pancreatitis were used as experimental models of acute pancreatitis in rats. Western blotting, RT-PCR and chromatin immunoprecipitations assay (Chip assay) techniques were used.

Results: The protein and mRNA GCS expression increased markedly in edematous pancreatitis, whereas in necrotizing pancreatitis it did not change. Recruitment of c-Myc and RNA polymerase II to the promoters and in the latter case also to exons of both GCS subunits occurred in both types of pancreatitis. However, in necrotizing pancreatitis there was a remarkably increase in cytosolic ribonuclease activity, which may account at least in part for the failure of GCS up-regulation in the severe form of the disease. No increase in ribonuclease activity was found in edematous pancreatitis.

Conclusion: In edematous pancreatitis there is marked up-regulation of GCS expression driven by c-Myc. However, in necrotizing pancreatitis ineffective induction of GCS occurs despite binding of c-Myc and RNA polymerase II to the promoters. This failure in up-regulation appears to be mediated by RNA degradation caused by increased cytosolic ribonuclease activity.