The oxidative biotransformation of losoxantrone (CI-941).
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.
Renner
Ulf D
UD
Medizinische Klinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany. renner@mk1.med.tu-dresden.de
Piperopoulos
Georgios
G
Gebhardt
Rolf
R
Ehninger
Gerhard
G
Zeller
Klaus-Peter
KP
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D018197:Hepatoblastoma / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008797:Metyrapone / Q000494:pharmacology; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D047069:Pyrazolones; D051381:Rats; D017207:Rats, Sprague-Dawley
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D008797:Metyrapone