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Comparaison des mécanismes de toxicité redox du cadmium, du cuivre et du zinc : place des métallothionéines et de p53

Yves Nzengue 1
1 LAN - Laboratoire Lésions des Acides Nucléiques
SCIB - UMR E3 - Service de Chimie Inorganique et Biologique : DSM/INAC/SCIB
Abstract : DNA damage induced by cadmium (Cd) come not only from various antioxidant molecules inactivation, but also from the interference of this metal with other systems involved an alteration of essential metals homeostasis such as zinc (Zn) and copper (Cu). To understand the involvement of oxidative stress in the mechanisms of toxicity induced by metals, we analyzed their impact on antioxidant balance (biomarkers of oxidative stress, the major antioxidant enzymes activities, synthesis of other antioxidants factors such as metallothionein and glutathione) of two cellular lines, a cell line derived from human keratinocytes and immortalized by p53 gene mutation (HaCaT), and a line issue of rat glioblastoma (C6). Our results are in favour of prooxidant effects. The results showed that the 3 metals affect the cells redox status. This is revealed by an increased of oxidized glutathione level (GSSG), MDA level, inducing DNA damage, and not only a decrease in protein thiols groups (SH) levels, glutathione (GSH) level, but also glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GRase) and superoxide dismutases (SODs) activities. The metals impact on the antioxidant enzymes activities is accompanied by an increase in free radicals concentrations such as the hydroxyl radical, which can initiates lipid peroxidation; proteins, GSH oxidation and DNA damage.
Unlike other metals, Cd up 50 µM has a relatively low toxicity in HaCaT cells. This resistance is mainly explained by the presence of metallothionein (MTs) in basal state on the one hand and a synthesis of GSH and MTs induced by Cd on the other hand. The MT expression induced by Cd, Cu or Zn and MTs nuclear translocation suggests DNA protection role of these MTs against oxidative damage. The expression of MTs is regulated not only by a synthesis metals-induced but also by the GSH and p53 protein levels whose mutation has an impact on intracellular MTs levels and impact on HaCaT resistance to Cd.
These studies indicate that the imbalance between inhibition of antioxidants activities and synthesis of other factors such as GSH and MTs is strongly involved in metals toxicities. This imbalance is the cause of the oxidative stress increasing and explains the C6 cells sensitivity and high mortality induced by Cd. In these C6 cells, the antioxidant enzymes activities, GSH and MTs levels decrease at 20 μM Cd and 475 µM Cu. This decrease is accompanied by an increased cell death. The cell death obtained after incubation with Cd, Cu or Zn is dose-dependent and very different between C6 and HaCaT lines. Indeed, HaCaT cells in the presence of Cd and Cu have a nonapoptotic death while C6 cells, incubated with Cd, die via a p53-dependent apoptosis.
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https://tel.archives-ouvertes.fr/tel-00281577
Contributor : Yves Nzengue <>
Submitted on : Friday, May 23, 2008 - 12:06:05 PM
Last modification on : Wednesday, November 4, 2020 - 2:07:28 PM
Long-term archiving on: : Friday, May 28, 2010 - 7:55:20 PM

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Yves Nzengue. Comparaison des mécanismes de toxicité redox du cadmium, du cuivre et du zinc : place des métallothionéines et de p53. Sciences du Vivant [q-bio]. Université Joseph-Fourier - Grenoble I, 2008. Français. ⟨tel-00281577⟩

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