SY-640

An immunological liver injury model was established by injection of micro lipopolysaccharide (LPS) into BCG (bacilli Calmette Guéin)-primed mice. It was found that nitric oxide (NO) played dual effects in the liver damage induced by BCG+LPS. The NO coming from phagocytic cells showed toxic effects while those from the other cells displayed beneficial effects. Tumor necrosis factor (TNF) released by macrophages was also implicated to be a key factor in the liver damage induced by BCG + LPS. Kupffer cells were involved in BCG + LPS-induced liver injury by releasing NO and TNF. The mechanism(s) by which the two new hepatoprotectants (SY-801 and SY-640) reduced BCG + LPS-induced liver damage may be through enhancing mouse plasma NO levels and lowering NO production and TNF expression by macrophages.

The hepatoprotective effect of SY-640 on Propionibacterium acnes and lipopolysaccharide-induced liver injury in mice and its protective mechanism were examined. Oral administration of SY-640, 150 mg/kg once daily for 7 days, significantly inhibited Propionibacterium acnes and lipopolysaccharide-induced liver injury, but a single administration was without effect. Liver-infiltrating cells (T-lymphocytes and macrophages) play an important role in Propionibacterium and lipopolysaccharide-induced liver injury and express a higher level of leukocyte function-associated antigen-1. SY-640 inhibited the number of liver-infiltrating cells and attenuated the increased expression of leukocyte function-associated antigen-1 on these cells. Tumor necrosis factor-alpha mediated Propionibacterium acnes and lipopolysaccharide-induced liver injury, and SY-640 inhibited the elevation of the serum tumor necrosis factor-alpha concentration after injection of lipopolysaccharide in Propionibacterium acnes-primed mice. The putative effects of SY-640 are inhibitory effects on infiltration into the liver and on activation of T-lymphocytes and macrophages after Propionibacterium acnes-priming, and attenuation of expression of cell adhesion molecules such as leukocyte function-associated antigen-1. The immunological effect of SY-640 is likely to be closely related to the inhibition of Propionibacterium and lipopolysaccharide-induced liver injury.