T. Nakatani et al., Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes, CHEM-BIO IN, 125(3), 2000, pp. 151-163
Zn2+ has multiple implications in cellular metabolism, including free radic
als metabolism and cell death by apoptosis. In the present study, we examin
ed the role of Zn2+. in the regulation of apoptosis in cultured rat hepatoc
ytes. The chelation of Zn2+ by a membrane permeable metal ion chelator, N,
N, N', N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), induced apoptos
is. Addition of ZnSO4 prevented TPEN-induced apoptosis. Unlike the effect o
f TPEN, a membrane impermeable metal ion chelator, diethylenetriamine penta
acetic acid (DTPA), did not induce apoptosis, indicating that chelation of
intracellular Zn2+ was required to trigger apoptosis, Caspase-3-like proteo
lytic activity, a general biochemical mediator of apoptosis in a variety of
cells and tissues, was also activated with the treatment of TPEN but not D
TPA. TPEN treatment, but not DTPA, also resulted in the depletion of intrac
ellular reduced glutathione (GSH) but addition of Zn2+ recovered the GSH le
vel. N-acetyl-L-cysteine (NAC), a thiol antioxidant, prevented TPEN-induced
apoptosis. These results taken together suggest that intracellular Zn2+ in
terfere with the apoptosis process, possibly through the regulation of cell
ular redox potential involving GSH. (C) 2000 Elsevier Science Ireland Ltd.
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