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Cadmium-induced non-apoptotic cell death mediated by oxidative stress under the condition of sulfhydryl deficiency.

Abstract：

:Cadmium (Cd), which accumulates primarily in the liver and the kidney, induces apoptosis and also causes necrotic cell death in certain pathophysiologic situations. Previously, we have shown that Cd activated mitogen-activated protein kinases and that sulfur amino acid deficiency potentiated Cd-induced cytotoxicity via activation of mitogen-activated protein kinases. In the present study, we established the mechanistic basis of apoptotic and non-apoptotic cell death induced by Cd in H4IIE cells a rat-derived hepatocyte cell line. Cd at 0.3-10 microM decreased viability of cells in a concentration-dependent manner. Cd-induced cytotoxicity was enhanced by pretreatment with buthionine sulfoximine (BSO). Cd at 0.3 microM induced translocation of Bad to mitochondria, decreased the level of mitochondrial BcL(XL) with the release of cytochrome c, and induced procaspase-9 activation and poly(ADP-ribose) polymerase (PARP) cleavage. Sulfhydryl deficiency by BSO, however, blocked PARP cleavage in spite of the decrease in procaspase-9. Cytochrome c release, procaspase-9 activation and PARP cleavage were all increased by 1 microM Cd irrespective of BSO pretreatment. We also used H(2)O(2) (10-100 microM) as a source of oxidative stress. Cd (0.3-1 microM) + H(2)O(2) (70 microM) resulted in greater extents of cytochrome c release, procaspase-9 activation and PARP cleavage in H4IIE cells than Cd alone. Flow cytometric analysis confirmed apoptotic and non-apoptotic cell death by Cd depending on cellular glutathione (GSH) content. These results provide evidence that Cd at the physiologically obtainable concentration causes non-apoptotic cell death under the condition of sufhydryl deficiency, whereas Cd at the micromolar level induces apoptosis. The cell death mechanism involves cytochrome c release from mitochondria and decrease in the level of procaspase-9, but not PARP cleavage, implying that alterations in cellular sulfhydryls may be the major determining factor for the path of cell death in response to low level of Cd.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Kim SC,Cho MK,Kim SG

doi

10.1016/s0378-4274(03)00233-9

keywords:

subject

Has Abstract

pub_date

2003-10-15 00:00:00

pages

325-36

issue

eissn

0378-4274

issn

1879-3169

pii

S0378427403002339

journal_volume

144

pub_type

杂志文章

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Cadmium-induced non-apoptotic cell death mediated by oxidative stress under the condition of sulfhydryl deficiency.