Zinc toxicity alters mitochondrial metabolism and leads to decreased ATP production in hepatocytes.

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada.
Journal of Applied Toxicology (Impact Factor: 3.17). 04/2008; 28(2):175-82. DOI: 10.1002/jat.1263
Source: PubMed

ABSTRACT Although zinc (Zn) is a known environmental toxicant, its impact on the cellular energy-producing machinery is not well established. This study investigated the influence of this divalent metal on the oxidative ATP producing network in human hepatocellular carcinoma (HepG2) cells. Zn-challenged cells contained more oxidized proteins and lipids compared with control cells. Zn severely impeded mitochondrial functions by inhibiting aconitase, alpha-ketoglutarate dehydrogenase, isocitrate dehydrogenase-NAD+ dependent, succinate dehydrogenase and cytochrome C oxidase Zn-exposed cells had a disparate mitochondrial metabolism compared with the control cells and produced significantly less ATP. However, the expression of isocitrate dehydrogenase-NADP+ dependent was more prominent in cells treated with Zn. Hence, Zn-induced pathologies may be due to the inability of the mitochondria to generate energy effectively.

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    ABSTRACT: The effects of Cadmium (Cd) exposure and the treatment with Zinc (Zn) on immune functions of splenocytes and cultured lymphocytes of rats were studied. The exposure of rats to Cd was at a dose of 2.2 mg/kg CdCl2, injected subcutaneously four times weekly for 2 months. Rats were supplemented with Zn (2.2 mg/kg ZnCl2, injected subcutaneously four times weekly for 2 months) one hour prior to Cd exposure. Spleens were removed and splenocytes were isolated and cultured. The proliferation capacity of lymphocytes and their homing to the spleen were studied. Ribonucleic acid (RNA) was extracted from stimulated lymphocytes in order to analyse gene expressions using RT-PCR. Accordingly, proliferation of lymphocytes was found to be suppressed in Cd-treated rats, both in vivo and in vitro. Zinc served to activate the proliferation of B and T lymphocytes in Cd-treated rats both in vivo and in vitro. Antigen-activated lymphocytes showed that Cd impaired the mRNA expression of CD68, Ccl22 and CXCL10. Zinc was not found to restore mRNA expression of these genes to the normal levels. Zinc was found to decrease the MDA level with replenishment of activity of key antioxidant enzymes and proteins in Cd-pre-treated animals significantly. Moreover, the histopathological examination of spleen samples also agreed with the molecular, immunological and redox findings. Hence, Zn is able to restore the normal structure, redox status and immunity in Cd-induced damage in the rat model system.
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