Reduction of the indoloquinone anticancer drug EO9 by purified DT-diaphorase: a detailed kinetic study and analysis of metabolites.

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 Pharmacol

journal_title

Biochemical pharmacology

authors

Bailey SM,Lewis AD,Knox RJ,Patterson LH,Fisher GR,Workman P

doi

10.1016/s0006-2952(97)00661-8

subject

Has Abstract

pub_date

1998-09-01 00:00:00

pages

613-21

issue

5

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(97)00661-8

journal_volume

56

pub_type

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