Abstract
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- andpara-hydroquinonoid substructure, respectively. The identification of a glutathione conjugate as a follow-up metabolite confirms the oxidative activation of theortho-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.
Footnotes
- Abbreviations used are::
- CI-941 or DuP-941
- 7-hydroxy-2-[2-[(2-hydroxyethyl)amino]ethyl]-5-[[2-[(2-hydroxyethyl)ami-no]ethyl]amino]-anthra[1,9-cd]pyrazol-6(2H)-one dihydrochloride
- LC-MS
- liquid chromatography-mass spectrometry
- HPLC
- high-performance liquid chromatography
- TOCSY
- total correlation spectroscopy
- HMQC
- heteronuclear multiple-quantum coherence spectroscopy
- HMBC
- heteronuclear multiple-bond correlation spectroscopy
- VIS
- visible
- RIC
- reconstructed ion current
- CID
- collision-induced dissociation
- MS/MS
- tandem mass spectrometry
- CI-937
- teloxantrone
- Received July 25, 2001.
- Accepted January 14, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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