Capella M A M, Capella L S, Valente R C, Gefé M, Lopes A G
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, RJ, Brazil.
Cell Biol Toxicol. 2007 Nov;23(6):413-20. doi: 10.1007/s10565-007-9003-4. Epub 2007 Apr 25.
Vanadium is an environmentally toxic metal with peculiar and sometimes contradictory cellular effects. It is insulin-mimetic, it can either stimulate cell growth or induce cell death, and it has both mutagenic and antineoplastic properties. However, the mechanisms involved in those effects are poorly understood. Several studies suggest that H(2)O(2) is involved in vanadate-induced cell death, but it is not known whether cellular sensitivity to vanadate is indeed related to H(2)O(2) generation. In the present study, the sensitivity of four cell lines from different origins (K562, K562-Lucena 1, MDCK, and Ma104) to vanadate and H(2)O(2) was evaluated and the production of H(2)O(2) by vanadate was analyzed by flow cytometry. We show that cell lines very resistant to H(2)O(2) (K562, K562-Lucena 1, and Ma104 cells) are much more sensitive to vanadate than MDCK, a cell line relatively susceptible to H(2)O(2), suggesting that vanadate-induced cytotoxicity is not directly related to H(2)O(2) responsiveness. In accordance, vanadate concentrations that reduced cellular viability to approximately 60-70% of the control (10 mumol/L) did not induce H(2)O(2) formation. A second hypothesis, that peroxovanadium (PV) compounds, produced once vanadate enters into the cells, are responsible for the cytotoxicity, was only partially confirmed because MDCK cells were resistant to both vanadate and PV compounds (10 micromol/L each). Therefore, our results suggest that vanadate toxicity occurs by two distinct pathways, one dependent on and one independent of H(2)O(2) production.
钒是一种对环境有毒的金属，具有独特且有时相互矛盾的细胞效应。它具有胰岛素模拟作用，既能刺激细胞生长，也能诱导细胞死亡，同时具有致突变和抗肿瘤特性。然而，这些效应所涉及的机制尚不清楚。多项研究表明，过氧化氢（H₂O₂）参与钒酸盐诱导的细胞死亡，但细胞对钒酸盐的敏感性是否确实与H₂O₂的产生有关尚不清楚。在本研究中，评估了四种不同来源的细胞系（K562、K562-Lucena 1、MDCK和Ma104）对钒酸盐和H₂O₂的敏感性，并通过流式细胞术分析了钒酸盐产生H₂O₂的情况。我们发现，对H₂O₂具有高度抗性的细胞系（K562、K562-Lucena 1和Ma104细胞）对钒酸盐的敏感性远高于MDCK细胞系（一种对H₂O₂相对敏感的细胞系），这表明钒酸盐诱导的细胞毒性与H₂O₂反应性没有直接关系。相应地，将细胞活力降低至对照的约60 - 70%的钒酸盐浓度（10 μmol/L）并未诱导H₂O₂的形成。另一种假设是，钒酸盐进入细胞后产生的过氧钒（PV）化合物是细胞毒性的原因，但这一假设仅得到部分证实，因为MDCK细胞对钒酸盐和PV化合物（均为10 μmol/L）均具有抗性。因此，我们的结果表明，钒酸盐毒性通过两种不同途径发生，一种依赖于H₂O₂的产生，另一种独立于H₂O₂的产生。
