title: Vildagliptin and its metabolite M20.7 induce the expression of S100A8 and S100A9 in human hepatoma HepG2 and leukemia HL-60 cells.
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.
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Karaki
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Atsuda
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D040501:Calgranulin A / Q000378:metabolism*; D040502:Calgranulin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000378:metabolism*; D020869:Gene Expression Profiling; D018922:HL-60 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects*; D051379:Mice; D046228:Microarray Analysis; D009570:Nitriles / Q000378:metabolism*; D011759:Pyrrolidines / Q000378:metabolism*; D000077597:Vildagliptin
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; C576329:S100A9 protein, mouse; C086145:S100a8 protein, mouse; D000077597:Vildagliptin; D000218:Adamantane