title: MicroRNA expression in the vildagliptin-treated two- and three-dimensional HepG2 cells.
abstract: Vildagliptin is an inhibitor of dipeptidyl peptidase-4 that is used for the treatment of type 2 diabetes mellitus. While vildagliptin can induce hepatic dysfunction in humans, the molecular mechanism has not been determined yet. Recent studies indicated that certain types of microRNA (miRNA) were linking to the development of drug-induced hepatotoxicity. In the present study, therefore, we identified hepatic miRNAs that were highly induced or reduced by the vildagliptin treatment in mice. MiR-222 and miR-877, toxicity-associated miRNAs, were induced 31- and 53-fold, respectively, by vildagliptin in the liver. While a number of miRNAs were significantly regulated by the orally treated vildagliptin in vivo, such regulation was not observed in the vildagliptin-treated HepG2 cells. In addition to the regular two-dimensional (2D) culture, we carried out the three-dimensional (3D) culturing of HepG2 cells. In the 3D-HepG2 cells, a significant reduction of miR-222 was observed compared to the expression level in 2D-HepG2 cells. A slight induction of miR-222 by vildagliptin was observed in the 3D-HepG2 cells, although miR-877 was not induced by vildagliptin even in the 3D-HepG2 cells. Further investigations are needed to overcome the discrepancy in the responsiveness of the miRNA expressions to vildagliptin between in vivo and in vitro.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan; Center for Clinical Pharmacy and Clinical Sciences, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Mitsugi
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Center for Clinical Pharmacy and Clinical Sciences, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Atsuda
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan. Electronic address: fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D035683:MicroRNAs; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane
keywords: 3D culture; DPP-4; HepG2 cells; Hepatotoxicity; Vildagliptin; miRNA