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 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.
Kwaśnicka-Crawford
Dorota A
DA
Graduate Program in Neuroscience, Department of Psychiatry and the Brain Research Centre, The University of British Columbia, Vancouver, Canada BC V6T 1Z3.
Vincent
Steven R
SR
D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D024483:Vitamin K 3 / Q000008:administration & dosage*
D005420:Flavoproteins; D029701:Saccharomyces cerevisiae Proteins; D024483:Vitamin K 3; C478386:NDOR1 protein, human; D010088:Oxidoreductases; C478395:DCS1 protein, S cerevisiae; D009699:N-Glycosyl Hydrolases