Vildagliptin is a potent, orally active inhibitor of dipeptidyl peptidase-4 (DPP-4) for the treatment of
type 2 diabetes mellitus. It has been reported that
vildagliptin can cause hepatic dysfunction in patients. However, the molecular-mechanism of
vildagliptin-induced
liver dysfunction has not been elucidated. In this study, we employed an expression microarray to determine hepatic genes that were highly regulated by
vildagliptin in mice. We found that pro-inflammatory S100
calcium-binding protein (S100) a8 and S100a9 were induced more than 5-fold by
vildagliptin in the mouse liver. We further examined the effects of
vildagliptin and its major metabolite M20.7 on the
mRNA expression levels of S100A8 and S100A9 in human
hepatoma HepG2 and
leukemia HL-60 cells. In HepG2 cells,
vildagliptin, M20.7, and
sitagliptin - another
DPP-4 inhibitor - induced S100A9
mRNA. In HL-60 cells, in contrast, S100A8 and S100A9 mRNAs were significantly induced by
vildagliptin and M20.7, but not by
sitagliptin. The release of S100A8/A9 complex in the cell culturing medium was observed in the HL-60 cells treated with
vildagliptin and M20.7. Therefore, the parental
vildagliptin- and M20.7-induced release of S100A8/A9 complex from immune cells, such as neutrophils, might be a contributing factor of
vildagliptin-associated
liver dysfunction in humans.