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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Crockett, Julie C. Rogers, Michael J. Räikkönen, Johanna Auriola, Seppo Mönkkönen, Jukka Mönkkönen, Hannu |
| Description | Author Affiliation: Räikkönen J ( Department of Pharmaceutics, University of Kuopio, Yliopistonranta 1 B, P.O. Box 1627, Kuopio FIN-70211, Finland. Johanna.Raikkonen@uku.fi) |
| Abstract | BACKGROUND AND PURPOSE: Bisphosphonates (BPs) are highly effective inhibitors of bone resorption. Nitrogen-containing bisphosphonates (N-BPs), such as zoledronic acid, induce the formation of a novel ATP analogue (1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester triphosphoric acid; ApppI), as a consequence of the inhibition of farnesyl pyrophosphate synthase and the accumulation of isopentenyl pyrophosphate (IPP). ApppI induces apoptosis, as do comparable metabolites of non-nitrogen-containing bisphosphonates (non-N-BPs). In order to further evaluate a pharmacological role for ApppI, we obtained more detailed data on IPP/ApppI formation in vivo and in vitro. Additionally, zoledronic acid-induced ApppI formation from IPP was compared with the metabolism of clodronate (a non-N-BP) to adenosine 5'(beta,gamma-dichloromethylene) triphosphate (AppCCl2p). EXPERIMENTAL APPROACH: After giving zoledronic acid in vivo to rabbits, IPP/ApppI formation and accumulation was assessed in isolated osteoclasts. The formation of ApppI from IPP was compared with the metabolism of clodronate in MCF-7 cells in vitro. IPP/ApppI and AppCCl2p levels in cell extracts were analysed by mass spectrometry. KEY RESULTS: Isopentenyl pyrophosphate/ApppI were formed in osteoclasts in vivo, after a single, clinically relevant dose of zoledronic acid. Furthermore, exposure of MCF-7 cells in vitro to zoledronic acid at varying times and concentrations induced time- and dose-dependent accumulation of IPP/ApppI. One hour pulse treatment was sufficient to cause IPP accumulation and subsequent ApppI formation, or the metabolism of clodronate into AppCCl2p. CONCLUSIONS AND IMPLICATIONS: This study provided the first conclusive evidence that pro-apoptotic ApppI is a biologically significant molecule, and demonstrated that IPP/ApppI analysis is a sensitive tool for investigating pathways involved in BP action. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 3 |
| Volume Number | 157 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2009-06-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Adenosine Triphosphate Analogs & Derivatives Biosynthesis Bone Density Conservation Agents Pharmacology Diphosphonates Hemiterpenes Imidazoles Osteoclasts Drug Effects Metabolism Animals Apoptosis Administration & Dosage Cell Line, Tumor Clodronic Acid In Vitro Techniques Organophosphorus Compounds Rabbits Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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