Koizumi T, Yokota T, Ohmori S, Kumagai H, Suzuki K T
Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Toxicology. 1995 Jan 6;95(1-3):11-7. doi: 10.1016/0300-483x(94)02865-r.
In order to gain further insight into the protective mechanism of metallothionein (MT) against Cd cytotoxicity, the effects of in vivo Zn- or Cd-pretreatment on the cytotoxicity and alteration in cellular pH induced by Cd were examined in isolated rat hepatocytes and testicular Leydig cells. These pretreatments both induced the synthesis of MT in the hepatocytes, but not in the Leydig cells. Both pretreatments alleviated Cd cytotoxicity in the hepatocytes. Cd- or Zn-pretreatment was also effective in preventing Cd-induced cellular acidification in hepatocytes but neither pretreatment was effective in Leydig cells. In fact, Cd-pretreatment stimulated acidification in Leydig cells. Exposure in vitro of hepatocytes from untreated rats to probenecid, an inhibitor of HCO3-/Cl- exchange, also ameliorated Cd-induced cellular acidification, suggesting an involvement of HCO3-/Cl- exchange in the preventive action of MT against Cd-induced acidification. These results suggest that Cd cytotoxicity in various cells may be initiated by alterations in plasma membrane ion transport systems such as the HCO3-/Cl- exchange and consequential cellular acidification. Induction of MT, therefore, may prevent Cd cytotoxicity, at least in rat hepatocytes, by preventing an alteration in ion transport at the plasma membrane as well as by intracytoplasmic binding of the metal molecules.
为了进一步深入了解金属硫蛋白（MT）对镉细胞毒性的保护机制，我们在分离的大鼠肝细胞和睾丸间质细胞中研究了体内锌或镉预处理对镉诱导的细胞毒性以及细胞内pH值变化的影响。这两种预处理均能诱导肝细胞中MT的合成，但对间质细胞则无此作用。两种预处理都减轻了肝细胞中的镉细胞毒性。镉或锌预处理在预防镉诱导的肝细胞酸化方面也有效，但对间质细胞均无效。实际上，镉预处理会刺激间质细胞的酸化。将未处理大鼠的肝细胞在体外暴露于丙磺舒（一种HCO3-/Cl-交换抑制剂），也能改善镉诱导的细胞酸化，这表明HCO3-/Cl-交换参与了MT对镉诱导酸化的预防作用。这些结果表明，各种细胞中的镉细胞毒性可能是由质膜离子转运系统（如HCO3-/Cl-交换）的改变以及随之而来的细胞酸化引发的。因此，MT的诱导可能通过防止质膜离子转运的改变以及金属分子的胞内结合，至少在大鼠肝细胞中预防镉细胞毒性。
