[Why does iron abrogate the cytotoxic effect of S-nitrosothiols on human and animal cultured cells?].
It was found that dinitrosyl iron complexes (DNIC) with thiol-containing ligands (cysteine or glutathione) of concentrations up to 1 mM produce no cytotoxic effect on cultured cells from human milk gland carcinoma (MCF-7). The cytotoxic action on MCF-7 cells was produced by S-nitrosocysteine: at a concentration of 1 mM, it induced the death of 50% cells. A more stable S-nitrosothiol, S-nitrosoglutathione, did not produce any cytotoxic effect at the same concentration. It is assumed that the negative action of nitrosocysteine is due to its rapid degradation, which results in the accumulation of large amounts of free NO molecules followed by their oxidation by superoxide ions to peroxynitrite, an efficient inhibitor of metabolic processes. These processes seem to be not characteristic of the more stable S-nitrosoglutathione. The cytotoxic effect of nitrosocysteine was completlly abrogated by the addition of 0.2 mM ferrous citrate complex to the medium. When S-nitrosoglutathione NO (0.5 mM) or S-nitrosoglutathione (0.5 mM) + Fe(2+)-citrate (0.2 mM) were added to the medium, protein-bound dinitrosyl iron complexes formed with the involvement of endogenous or exogenous iron were detected in cells. The amount of the complexes in the presence of exogenous iron increased four times, reaching the value of 1.6 nmole/5 x 10(6) cells. Therefore, it was proposed that the blockade of the cytotoxic action of S-nitrosoglutathione by iron complexes is due to Cys-NO transformation of S-nitrosocysteine into dinitrosyl iron complexes. The high stability of these complexes ensures only a gradual accumulation of nitric oxide in cells.
Serezhenkov
V A
VA
Kalinina
E V
EV
Glazunova
V A
VA
Saprin
A N
AN
Vanin
A F
AF
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism*; D026422:S-Nitrosoglutathione / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*
D009589:Nitrogen Oxides; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C073661:dinitrosyl iron complex; D007501:Iron; D003545:Cysteine