Abstract：
:DT-diaphorase has been implicated in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9. Here, we have used a highly purified DT-diaphorase isolated from rat Walker tumour cells to provide unambiguous evidence for the ability of this enzyme to catalyze reduction of EO9 and to provide a more detailed characterization of the reaction. Under the conditions used hypoxia had no effect on the initial rate of this reduction but did effect the nature and stability of metabolites formed. Electron spin resonance (ESR) spectrometry studies showed that DT-diaphorase reduced EO9 to a highly oxygen-sensitive metabolite that is probably the hydroquinone. In the presence of air, this metabolite is auto-oxidized to generate both drug- and oxygen-based radicals. Comproportionation:disproportionation reactions may also be involved in the generation of these radical species. The identification of these metabolites may contribute to the understanding of the molecular mechanism of DNA damage and cytotoxicity exerted by EO9.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Bailey SM,Lewis AD,Knox RJ,Patterson LH,Fisher GR,Workman Pdoi
10.1016/s0006-2952(97)00661-8subject
Has Abstractpub_date
1998-09-01 00:00:00pages
613-21issue
5eissn
0006-2952issn
1873-2968pii
S0006-2952(97)00661-8journal_volume
56pub_type
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