Abstract
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.
Highlights
Drug-induced liver injury is a rare but serious adverse reaction and the most frequent reason for withdrawal from the market
We found that metallothionein (Mt) 1, Mt2, S100a8, and S100a9 were induced more than 5-fold by vildagliptin in mouse liver
To evaluate the changes in gene expression determined by expression array analysis, we performed real-time reverse transcription-polymerase chain reaction (RT-PCR) for Mt1, Mt2, S100a8, and S100a9 mRNA using hepatic total RNA of control and vildagliptin (1000 mg/kg)-treated mice
Summary
Drug-induced liver injury is a rare but serious adverse reaction and the most frequent reason for withdrawal from the market. A number of immune- and inflammation-related factors, such as S100 calcium-binding protein (S100), cytokines, and chemokines, have been implicated in the pathogenesis of drug-induced liver injury[10,11,12,13]. Fold change (Vildagliptin/Control) has been suggested that the induction of the inflammation-associated genes, including S100A8, S100A9, tumor necrosis factor-α(TNF-α), and interleukin-8, by drug and/or its metabolites is involved in drug-induced liver injury[11,12,14,15,16,17]. We examined the effects of vildagliptin and M20.7 on mRNA expression levels of inflammation-associated genes, such as S100A8, S100A9, and TNF-α, in human hepatoma HepG2 and monocytic HL-60 cells. We examined the effects of vildagliptin and M20.7 on the release of S100A8/A9 complex from the human cell lines
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