title: Zoledronic acid-induced IPP/ApppI production in vivo.
abstract: Bisphosphonates are currently the most important class of anti-resorptive drugs used for the treatment of diseases involving excess bone resorption. Recently we discovered a new mechanism of action for bisphosphonates. Previously it has been shown that nitrogen-containing bisphosphonates (N-BPs) are not metabolized. However, our studies revealed that N-BPs induce formation of a novel pro-apoptotic ATP analog (ApppI), as a consequence of the inhibition of FPP synthase in the mevalonate pathway, and the subsequent accumulation of isopentenyl pyrophosphate (IPP) in vitro. The primary aim of the current study was to determine whether zoledronic acid (a N-BP) induces IPP/ApppI formation in vivo. Mass spectrometry was used to identify whether in vivo administration of zoledronic acid-induced IPP/ApppI production by mouse peritoneal macrophages or bone marrow cells. IPP/ApppI could be detected in extracts from peritoneal macrophages isolated from zoledronic acid-treated animals. Increasing IPP/ApppI accumulation was determined up to 7 days after drug injection, indicating prolonged FPP synthase inhibition by zoledronic acid. Importantly, this is the first report of in vivo production of ApppI, supporting the biological significance of this molecule.
authors.affiliation: Department of Pharmaceutics, University of Kuopio, Finland. hannu.monkkonen@uku.fi
authors.forename: Hannu
authors.initials: H
authors.lastname: Mönkkönen
authors.forename: Penelope D
authors.initials: PD
authors.lastname: Ottewell
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuokkanen
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000378:metabolism; D045782:Hemiterpenes / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D009943:Organophosphorus Compounds; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D009943:Organophosphorus Compounds; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D000255:Adenosine Triphosphate; D051228:Geranyltranstransferase; D008798:Mevalonic Acid