Role of a novel dual flavin reductase (NR1) and an associated histidine triad protein (DCS-1) in menadione-induced cytotoxicity

Microsomal cytochrome P450 reductase catalyzes the one-electron transfer from NADPH via FAD and FMN to various electron acceptors, such as cytochrome P450s or to some anti-cancer quinone drugs. This results in generation of free radicals and toxic oxygen metabolites, which can contribute to the cyto...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2005-10, Vol.336 (2), p.565-571
Main Authors: Kwaśnicka-Crawford, Dorota A., Vincent, Steven R.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
APOPTOSIS
BENZOQUINONES
BINDING ENERGY
Cell Line
Cell Survival - drug effects
Cell Survival - physiology
Dose-Response Relationship, Drug
DRUGS
ELECTRON TRANSFER
Flavoproteins
Flavoproteins - genetics
Flavoproteins - metabolism
HISTIDINE
Humans
Kidney - cytology
Kidney - drug effects
Kidney - metabolism
KIDNEYS
METABOLITES
Microsomal cytochrome P450 reductase
N-Glycosyl Hydrolases - genetics
N-Glycosyl Hydrolases - metabolism
NADPH-dependent flavin reductase
NEOPLASMS
Oxidoreductases - genetics
Oxidoreductases - metabolism
PROTEINS
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Signal Transduction - drug effects
Signal Transduction - physiology
TOXICITY
Vitamin K 3 - administration & dosage
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Summary:Microsomal cytochrome P450 reductase catalyzes the one-electron transfer from NADPH via FAD and FMN to various electron acceptors, such as cytochrome P450s or to some anti-cancer quinone drugs. This results in generation of free radicals and toxic oxygen metabolites, which can contribute to the cytotoxicity of these compounds. Recently, a cytosolic NADPH-dependent flavin reductase, NR1, has been described which is highly homologous to the microsomal cytochrome P450 reductase. In this study, we show that over-expression of NR1 in human embryonic kidney cells enhances the cytotoxic action of the model quinone, menadione. Furthermore, we show that a novel human histidine triad protein DCS-1, which is expressed together with NR1 in many tissues, can significantly reduce menadione-induced cytotoxicity in these cells. We also show that DCS-1 binds NF1 and directly modulates its activity. These results suggest that NR1 may play a role in carcinogenicity and cell death associated with one-electron reductions.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2005.08.129