Differential effects of pyrrolidine dithiocarbamate on TNF-α-mediated liver injury in two different models of fulminant hepatitis

Background/Aims Pyrrolidine dithiocarbamate (PDTC) is an inhibitor of nuclear factor kappa B (NF-κB) activation. The present study aimed to investigate the effects of PDTC on lipopolysaccharide (LPS)-induced liver injury in two different models of fulminant hepatitis. Methods Mice infected with Bacillus Calmette Guerin (BCG) were challenged with LPS (0.2 mg/kg) to induce the model of inflammatory liver injury. Mice were injected with d-galactosamine (GalN, 600 mg/kg) and LPS (20 μg/kg) to induce the model of apoptotic liver injury. In the treatment groups, mice were pre-treated with PDTC (100 mg/kg), initiated 24 h prior to LPS. Results PDTC pretreatment reduced the infiltration of inflammatory cells, inhibited NF-κB activation and the expression of tumor necrosis factor alpha (TNF-α), attenuated nitric oxide production, and alleviated hepatic glutathione depletion. Correspondingly, PDTC reduced serum alanine aminotransferase, improved hepatic necrosis, and prolonged the survival in the BCG/LPS model. Conversely, PDTC accelerated death and aggravated liver apoptosis in the GalN/LPS model, although it reduced nitric oxide production, attenuated glutathione depletion, and inhibited the expression of TNF-α in liver. Conclusions PDTC protects mice against BCG/LPS-induced inflammatory liver injury through the repression of NF-κB-mediated TNF-α release, while it seems to be detrimental in GalN/LPS-induced apoptotic liver damage.