Renner Ulf D, Piperopoulos Georgios, Gebhardt Rolf, Ehninger Gerhard, Zeller Klaus-Peter
Medizinische Klinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
Drug Metab Dispos. 2002 Apr;30(4):464-78. doi: 10.1124/dmd.30.4.464.
The oxidative biotransformation of the anticancer drug 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-hydroxyethyl)amino]ethyl]amino]anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride (losoxantrone, CI-941) after incubation of primary cultures of rat hepatocytes has been investigated. The structures of twelve losoxantrone metabolites have been elucidated by means of high-performance liquid chromatography-mass spectometry, tandem mass spectrometry, and two-dimensional NMR. In these mammalian hepatocytes, the CI-941 biotransformation includes a monohydroxylation of the phenolic substructure of the CI-941-chromophore via cytochrome P450 catalysis, resulting in metabolites having an ortho- and para-hydroquinonoid substructure, respectively. The identification of a glutathione conjugate as a follow-up metabolite confirms the oxidative activation of the ortho-hydroxylated losoxantrone metabolite. The oxidative activation establishes the ability of CI-941 to form covalent bonds to intracellular nucleophilic targets. Furthermore, the CI-941 metabolism was shown to be extremely suppressed in rat hepatocytes incubated with metyrapone. In contrast to these results, human tumor HepG2 cells did not show any CI-941 biotransformation after incubation.
对大鼠肝细胞原代培养物进行孵育后，研究了抗癌药物7-羟基-2-[2-[(2-羟乙基)氨基]乙基]-5-[[2-[(2-羟乙基)氨基]乙基]氨基]蒽并[1,9-cd]吡唑-6(2H)-酮二盐酸盐（洛索蒽醌，CI-941）的氧化生物转化。通过高效液相色谱-质谱法、串联质谱法和二维核磁共振法阐明了12种洛索蒽醌代谢物的结构。在这些哺乳动物肝细胞中，CI-941的生物转化包括通过细胞色素P450催化对CI-941发色团的酚类亚结构进行单羟基化，分别产生具有邻苯二酚和对苯二酚亚结构的代谢物。鉴定出谷胱甘肽缀合物作为后续代谢物，证实了邻羟基化洛索蒽醌代谢物的氧化活化。氧化活化确立了CI-941与细胞内亲核靶点形成共价键的能力。此外，在用美替拉酮孵育的大鼠肝细胞中，CI-941的代谢被证明受到极大抑制。与这些结果相反，人肿瘤HepG2细胞在孵育后未显示任何CI-941生物转化。
