Liu J, Liu Y, Michalska A E, Choo K H, Klaassen C D
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
J Pharmacol Exp Ther. 1996 Mar;276(3):1216-23.
Metallothioneins (MTs) are low-molecular weight, cysteine-rich, metal-binding proteins. Pretreatment of animals with Zn increases tissue MT concentrations, and protects against Cd-induced toxicity. However, Zn treatment produces many effects in addition to increasing MT. Therefore, MT-I and -II knock-out (MT-null) mice were used to determine the roles of MT in Cd-induced hepatotoxicity and nephrotoxicity, as well as in Zn-induced protection. MT-null mice were more sensitive to CdCl2 (25 mumol/kg i.p.) hepatotoxicity, as evidenced by 25-fold increases in serum alanine aminotransferase activity, compared to 12-fold increases in control mice. Zn pretreatment (200 mumol/kg s.c. x 2 days) increased hepatic MT 80 fold in control mice but not in MT-null mice, and prevented CdCl2 hepatotoxicity in control mice only. It is concluded that MT plays a critical role in Cd-induced hepatotoxicity. In contrast to CdCl2-induced hepatotoxicity, MT-null mice were equally susceptible as controls to the Cd-MT (CdMT) (0.1-0.4 mg Cd/kg i.v.) nephrotoxicity, as evidenced by similar increases in urinary protein (up to 30-fold) and glucose excretion (up to 60-fold), as well as similar extent of proximal tubular necrosis. Zn increased renal MT (28-fold) in control mice only; however, it protected against CdMT-induced renal injury in both control and MT-null mice. These findings suggest that MT plays less of a protective role in protecting against CdMT-induced nephrotoxicity than CdCl2-induced hepatotoxicity, and that Zn-induced protection against CdMT-induced nephrotoxicity does not appear to be mediated through MT.
金属硫蛋白（MTs）是一类低分子量、富含半胱氨酸的金属结合蛋白。用锌对动物进行预处理可提高组织中MT的浓度，并预防镉诱导的毒性。然而，锌处理除了增加MT外还会产生许多其他影响。因此，利用MT-I和-II基因敲除（MT缺失）小鼠来确定MT在镉诱导的肝毒性和肾毒性以及锌诱导的保护作用中的作用。MT缺失小鼠对氯化镉（25 μmol/kg腹腔注射）肝毒性更敏感，血清丙氨酸转氨酶活性增加了25倍，而对照小鼠仅增加了12倍。锌预处理（200 μmol/kg皮下注射×2天）使对照小鼠肝脏MT增加了80倍，但MT缺失小鼠未增加，且仅预防了对照小鼠的氯化镉肝毒性。结论是MT在镉诱导的肝毒性中起关键作用。与氯化镉诱导的肝毒性相反，MT缺失小鼠对镉-金属硫蛋白（CdMT）（0.1 - 0.4 mg镉/kg静脉注射）肾毒性的易感性与对照小鼠相同，尿蛋白（高达30倍）和葡萄糖排泄（高达60倍）的类似增加以及近端肾小管坏死的相似程度证明了这一点。锌仅使对照小鼠肾脏MT增加（28倍）；然而，它对对照小鼠和MT缺失小鼠的CdMT诱导的肾损伤均有保护作用。这些发现表明，MT在预防CdMT诱导的肾毒性方面的保护作用比在预防氯化镉诱导的肝毒性方面要小，并且锌诱导的对CdMT诱导的肾毒性的保护作用似乎不是通过MT介导的。
