Sx. Liu et al., Nitric oxide-dependent pro-oxidant and pro-apoptotic effect of metallothioneins in HL-60 cells challenged with cupric nitrilotriacetate, BIOCHEM J, 354, 2001, pp. 397-406
Intracellular safeguarding functions of metallothioneins (MTs) include sequ
estering transition and heavy metals, scavenging free radicals and protecti
ng against electrophiles. We report that MT protection against Cu-induced c
ytotoxicity can be reversed and pro-oxidant and pro-apoptotic effects can b
e induced in HL-60 cells exposed to NO. We demonstrate that in ZnCl2-pretre
ated HL-60 cells loaded with copper nitrilotriacetate (Cu-NTA), exposure to
an NO donor, S-nitroso-N-acetyl penicillamine resulted in S-nitrosylation
and oxidation of MT cysteines. This disruption of MT Cu-binding thiolate cl
usters caused loosening and release of redox-active Cu, enhanced redox-cycl
ing activity of Cu and increased peroxidation of major classes of membrane
phospholipids. We also found that Cu-induced oxidative stress in ZnCl2-pret
reated/Cu-NTA-loaded HL-60 cells was accompanied by apoptosis documented by
characteristic changes of nuclear morphology, internucleosomal DNA cleavag
e, externalization of phosphatidylserine, release of cytochrome c from mito
chondria into cytosol and activation of caspase-3. We conclude that in Cu-c
hallenged cells, NO can reverse the protective role of MTs and convert them
into pro-oxidant, pro-apoptotic implements.