Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species

Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase...

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Veröffentlicht in:Biochemical pharmacology 2001-08, Vol.62 (4), p.461-468
Hauptverfasser: Bailey, Susan M., Lewis, Alex D., Patterson, Laurence H., Fisher, Geoff R., Knox, Richard J., Workman, Paul
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container_end_page 468
container_issue 4
container_start_page 461
container_title Biochemical pharmacology
container_volume 62
creator Bailey, Susan M.
Lewis, Alex D.
Patterson, Laurence H.
Fisher, Geoff R.
Knox, Richard J.
Workman, Paul
description Evidence suggests that DT-diaphorase is involved in the activation and mechanism of cytotoxicity of the investigational indoloquinone anticancer drug EO9 under aerobic conditions. Data also implicate a role for other enzymes including NADPH: cytochrome P450 reductase, especially in low DT-diaphorase tumour cells and under hypoxic conditions. Here, we used purified rat NADPH: cytochrome P450 reductase to provide additional evidence in support of a role for this enzyme in activation of EO9 to generate free radical and DNA-damaging species. Electron spin resonance spectrometry studies showed that NADPH: cytochrome P450 reductase reduced EO9 to a free radical species, including a drug radical (most likely the semiquinone) and reactive oxygen species. Plasmid DNA experiments showed that reduction of EO9 catalysed by NADPH: cytochrome P450 reductase results in single-strand breaks in DNA. The information obtained may contribute to the understanding of the molecular mechanism of DNA damage and cytotoxicity exerted by EO9 and may be useful in the design of future bioreductive drugs.
doi_str_mv 10.1016/S0006-2952(01)00674-8
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subjects Animals
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Aziridines - metabolism
Aziridines - pharmacology
Biological and medical sciences
Bioreductive agents
Catalysis
DNA - drug effects
DNA - metabolism
DNA Damage
Drug toxicity and drugs side effects treatment
Electron Spin Resonance Spectroscopy
EO9
Free Radicals - pharmacology
Indolequinones
Indoles - metabolism
Indoles - pharmacology
Medical sciences
Miscellaneous (drug allergy, mutagens, teratogens...)
NADPH-Ferrihemoprotein Reductase - metabolism
NADPH: cytochrome P450 reductase
Pharmacology. Drug treatments
Rats
Reduction
title Involvement of NADPH: cytochrome P450 reductase in the activation of indoloquinone EO9 to free radical and DNA damaging species
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