Protective effect of polaprezinc on cadmium-induced injury of lung epithelium.

Cadmium is a toxic metal contained in food, water and the atmosphere, and exposure to cadmium can cause respiratory diseases in humans. Various health problems caused by cadmium result from oxidative stress-dependent cellular injury. Metallothioneins are intracellular, cysteine-rich, metal-binding proteins that have a detoxifying action on heavy metals such as cadmium in various organs. In addition, expression of metallothioneins is induced by metals with low biological toxicity, such as zinc. Therefore, in this study we examined whether polaprezinc, a chelate compound consisting of carnosine and zinc, can suppress cadmium-induced lung epithelial cell death. We found that cell viability markers (intracellular ATP levels and mitochondrial activity) and cytotoxicity (lactate dehydrogenase release) were decreased and increased, respectively by cadmium treatment; however, polaprezinc significantly reversed these changes. Moreover, cadmium-dependent endoplasmic reticulum stress responses were suppressed by polaprezinc treatment. We then examined the protective mechanisms of polaprezinc, focusing on oxidative stress. Cadmium induced the production of reactive oxygen species (ROS) in A549 cells in a dose-dependent manner and polaprezinc significantly suppressed this cadmium-induced ROS production. Finally, we examined whether polaprezinc exerts an antioxidative action by inducing metallothioneins. We found that polaprezinc dose-dependently induced metallothioneins using real-time RT-PCR, ELISA, and western blotting analyses. These results indicate that polaprezinc can suppress cadmium-induced lung epithelial cell death and oxidative stress by inducing metallothioneins. We therefore suggest that polaprezinc may have therapeutic effects against respiratory diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Role of Na+, K+-ATPase alpha1 subunit in the intracellular accumulation of cisplatin.

The present study was undertaken to identify what regulates intracellular cisplatin (CDDP) accumulation and what changes in membrane fraction of CDDDP-resistant cell line. The CDDP-resistant rat hepatoma cell line, H4-II-E/CDDP, shows a significant decrease in intracellular platinum accumulation compared with parental H4-II-E cells, although there was no difference in the efflux of CDDP between these two cell lines. In this study, we examined the contribution of functional change in active transport to the CDDP resistance of H4-II-E/CDDP cells. Compared with the resistant cells, platinum accumulation in the parental cells was clearly decreased by low temperature or ATP depletion. In addition, the Na+, K+-ATPase inhibitor ouabain and the K+ channel inhibitor tetraethylammonium decreased platinum accumulation in parental cells but did not change the accumulation in resistant cells. Amphotericin B, an antifungal agent, increased the intracellular platinum accumulation in resistant cells to the same level as in parent cells. Western blot analysis demonstrated that the Na+, K+-ATPase alpha1 subunit was reduced in resistant cells compared with the parental cells, although there was no difference in the expression of the beta1 subunit between the two cell lines. Furthermore, the Na+, K+-ATPase alpha1 subunit of H4-II-E was decreased following a 24-h exposure to CDDP. These results suggest that Na+, K+-ATPase-dependent active transport of CDDP does not occur in resistant cells, and, furthermore, our findings provide the first evidence that the Na+, K+-ATPase alpha1 subunit plays an important role in the transport of CDDP.