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B
Department of Biochemistry, Mount Sinai School of Medicine, New
York, New York 10029
Menadione (vitamin K-3,2-methyl-1,4-naphthoquinone), a redox cycling
reagent, generates reactive oxygen intermediates and causes oxidative
injury. The addition of menadione to Hep G2 cells produced a time- and
concentration-dependent loss of cell viability. Preincubation of Hep G2
cells with low, nontoxic concentrations of menadione increased the
viability of the cells against toxic doses of menadione or
H2O2. Maximum protection was found with menadione concentrations of ~3 µM and preincubation
times of ~45 min. This protective effect could be blocked by the
protein synthesis inhibitor cycloheximide and by a variety of
antioxidants. The transcription factor nuclear factor-
F (NF-B) is
known to be activated by many compounds, including reactive oxygen
intermediates. Menadione activated NF-B as determined by
electrophoretic mobility shift assays. This activation was prevented by
the same antioxidants that blocked protection against cytotoxicity
produced by preincubation with menadione. Anti-p50 IgG prevented the
menadione-stimulated binding of NF-B to the oligonucleotide probe,
whereas anti-p65 IgG produced a supershift of the
NF-B/oligonucleotide complex. Salicylate prevented the activation of
NF-B by menadione, and under these conditions, salicylate
potentiated the cytotoxicity of menadione or
H2O2. Transfection with a plasmid containing
cDNA encoding mouse IB
, an inhibitor of NF-B, resulted in
increased toxicity by menadione. Furthermore, when protein kinase C was down-regulated by prolonged treatment with active phorbol ester (phorbol-12-myristate-13-acetate), the Hep G2 cells became more sensitive to menadione treatment. However, short term treatment with
PMA, which activated NF-B, resulted in protection against menadione
cytotoxicity. Menadione cytotoxicity was enhanced when the Hep G2 cells
were depleted of GSH. An increased level of GSH was observed after
menadione pretreatment; this increase was blocked by salicylate,
thereby linking the GSH increase to activation of NF-B by menadione.
The results of the current study suggest that menadione pretreatment
protects Hep G2 cells from oxidative injury through an NF-B-related
mechanism, which may involve, in part, increased production of GSH.
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