Tang W, Sadovic S, Shaikh Z A
College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Toxicol Appl Pharmacol. 1998 Aug;151(2):276-82. doi: 10.1006/taap.1998.8465.
Chronic cadmium (Cd) exposure can cause renal proximal tubular dysfunction resulting from the release of Cd metallothionein (CdMT) from the liver and its accumulation and degradation in the renal tubular epithelial cells. Pretreatment with zinc (Zn) can protect against acute CdMT nephrotoxicity. While induction of MT by Zn plays a part in Zn protection, other factors, such as glutathione (GSH), may also be involved because protection is offered even in MT-null mice. The present study was designed to investigate the involvement of GSH in Zn protection against acute CdMT nephrotoxicity. The study was carried out in MT-null mice to remove the induction of MT by Zn as a confounding variable. Three approaches were used to modulate renal cortex GSH levels: buthionine sulfoximine (BSO) was administered to inhibit GSH synthesis, and GSH and Zn were administered to increase the GSH levels. Both GSH and Zn were effective in protecting against CdMT nephrotoxicity. Elevation in renal cortex GSH levels, however, was not essential for Zn protection, as a low dose of Zn that caused no significant increase in renal GSH also protected against CdMT. On the other hand, maintenance of normal GSH status was essential for Zn protection, as inhibition of GSH synthesis abolished this protection. Both GSH and Zn reduced the accumulation of Cd as well as MT in the renal cortex, with Zn causing greater reduction in Cd accumulation than that of MT. The relative intracellular distribution of Cd was unaltered. These results suggest that in MT-null mice Zn protects against CdMT nephrotoxicity by possibly displacing some of the Cd from CdMT as well as reducing the uptake of CdMT, and that this protection requires the maintenance of normal GSH status.
长期接触镉（Cd）可导致肾近端小管功能障碍，这是由于肝脏释放镉金属硫蛋白（CdMT）并在肾小管上皮细胞中蓄积和降解所致。锌（Zn）预处理可预防急性CdMT肾毒性。虽然锌诱导金属硫蛋白（MT）在锌的保护作用中发挥了一定作用，但其他因素，如谷胱甘肽（GSH），也可能参与其中，因为即使在MT基因敲除小鼠中也能提供保护作用。本研究旨在探讨GSH在锌对急性CdMT肾毒性的保护作用中的参与情况。该研究在MT基因敲除小鼠中进行，以消除锌诱导MT作为一个混杂变量的影响。采用三种方法调节肾皮质GSH水平：给予丁硫氨酸亚砜胺（BSO）抑制GSH合成，给予GSH和锌以提高GSH水平。GSH和锌均能有效预防CdMT肾毒性。然而，肾皮质GSH水平的升高对于锌的保护作用并非必不可少，因为低剂量的锌并未导致肾GSH显著增加，但也能预防CdMT。另一方面，维持正常的GSH状态对于锌的保护作用至关重要，因为抑制GSH合成会消除这种保护作用。GSH和锌均降低了肾皮质中Cd以及MT的蓄积，锌导致的Cd蓄积减少幅度大于MT。Cd的相对细胞内分布未改变。这些结果表明，在MT基因敲除小鼠中，锌通过可能将一些Cd从CdMT中置换出来以及减少CdMT的摄取来预防CdMT肾毒性，并且这种保护作用需要维持正常的GSH状态。
