Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.
Environ Toxicol. 2010 Oct;25(5):456-67. doi: 10.1002/tox.20590.
Thallium (Tl) is a highly toxic heavy metal though up to now its mechanisms are poorly understood. In this study, we comparatively investigated the cytotoxic mechanisms of Tl(I) and Tl(III) in isolated rat hepatocytes. Both Tl(I) and Tl(III) cytotoxicities were associated with reactive oxygen species (ROS) formation, lipid peroxidation, collapse of mitochondrial membrane potential, activation of caspases cascade, lysosomal membrane leakiness, and cellular proteolysis. Hepatocyte glutathione (GSH) was also rapidly oxidized. GSH-depleted hepatocytes were more resistant to Tl(I)-induced cytotoxicity, ROS formation and lipid peroxidation. This suggests that Tl(I) is reductively activated by GSH. On the other hand, GSH-depleted hepatocytes were much more sensitive to Tl(III)-induced cytotoxicity, ROS formation, and lipid peroxidation. This suggests that GSH only plays an antioxidant role against Tl(III) cytotoxicity. Our results also showed that CYP2E1 involves in Tl(I) and Tl(III) oxidative stress cytotoxicity mechanism and both cations detoxified via methylation. In conclusion, both Tl(I) and Tl(III) cytotoxicities were associated with mutual mitochondrial/lysosomal injuries (cross-talk) initiated by increased ROS formation resulted from metal-CYP2E1 destructive interaction or metal-induced disruption of mitochondrial electron transfer chain.
铊（Tl）是一种剧毒重金属，尽管迄今为止其机制仍未得到很好的理解。在这项研究中，我们比较研究了 Tl（I）和 Tl（III）在分离的大鼠肝细胞中的细胞毒性机制。Tl（I）和 Tl（III）的细胞毒性均与活性氧（ROS）形成、脂质过氧化、线粒体膜电位崩溃、半胱天冬酶级联激活、溶酶体膜通透性增加以及细胞蛋白水解有关。肝细胞谷胱甘肽（GSH）也迅速氧化。GSH 耗竭的肝细胞对 Tl（I）诱导的细胞毒性、ROS 形成和脂质过氧化的抵抗力更强。这表明 Tl（I）被 GSH 还原激活。另一方面，GSH 耗竭的肝细胞对 Tl（III）诱导的细胞毒性、ROS 形成和脂质过氧化更为敏感。这表明 GSH 仅对 Tl（III）的细胞毒性起抗氧化作用。我们的结果还表明，CYP2E1 参与了 Tl（I）和 Tl（III）的氧化应激细胞毒性机制，两种阳离子均通过甲基化解毒。总之，Tl（I）和 Tl（III）的细胞毒性均与相互的线粒体/溶酶体损伤（串扰）有关，这是由金属-CYP2E1 破坏性相互作用或金属诱导的线粒体电子传递链破坏导致的 ROS 形成增加引起的。
