Mönkkönen Hannu, Ottewell Penelope D, Kuokkanen Johanna, Mönkkönen Jukka, Auriola Seppo, Holen Ingunn
Department of Pharmaceutics, University of Kuopio, Finland.
Life Sci. 2007 Sep 8;81(13):1066-70. doi: 10.1016/j.lfs.2007.08.007. Epub 2007 Aug 17.
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.
双膦酸盐类药物是目前用于治疗涉及骨吸收过多疾病的最重要的抗骨吸收药物类别。最近我们发现了双膦酸盐类药物的一种新作用机制。此前已表明含氮双膦酸盐（N-BPs）不会被代谢。然而，我们的研究表明，N-BPs会诱导一种新型促凋亡ATP类似物（ApppI）的形成，这是由于甲羟戊酸途径中FPP合酶受到抑制，以及随后体外异戊烯基焦磷酸（IPP）积累的结果。本研究的主要目的是确定唑来膦酸（一种N-BP）是否在体内诱导IPP/ApppI的形成。采用质谱法来鉴定唑来膦酸体内给药是否能诱导小鼠腹腔巨噬细胞或骨髓细胞产生IPP/ApppI。在从经唑来膦酸处理的动物分离出的腹腔巨噬细胞提取物中可检测到IPP/ApppI。在药物注射后长达7天内都能测定到IPP/ApppI积累的增加，这表明唑来膦酸对FPP合酶的抑制作用持续时间较长。重要的是，这是关于ApppI体内产生的首次报道，支持了该分子的生物学意义。
