Klaassen C D, Liu J
Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City 66160, USA.
J Toxicol Sci. 1998 Jul;23 Suppl 2:97-102. doi: 10.2131/jts.23.supplementii_97.
The role of MT in Cd toxicology has become clearer by the use of MT-I transgenic and MT-I and -II knock-out animals. We have shown that: (1) MT-transgenic and -null mice have altered tissue MT protein levels; (2) MT-transgenic and -null mice appear to be normal in other detoxifying systems examined, except for slight alterations in tissue Zn concentration; (3) MT does not appear to inhibit Cd absorption from the gastrointestinal tract, nor affect Cd tissue distribution; (4) MT reduces the elimination of Cd from liver; (5) MT protects against acute inorganic Cd-induced lethality and hepatotoxicity, and the mechanism of the protection appears to be due to its ability to sequester Cd in the cytosol, thus reducing the amount of Cd in critical organelles; (6) MT modulates Cd-induced expression of protooncogene(c-jin) and tumor suppress genes (p53) in mouse liver; (7) MT does not protect against CdMT-induced acute renal injury, and Zn-induced protection against CdMT-induced acute nephrotoxicity does not appear to be mediated through MT; (8) Chronic Cd administration produces renal injury inb MT-null mice, indicating that Cd-induced nephrotoxicity is not necessarily mediated through the CdMT complex; (9) MT protects against chronic CdC12 nephropathy, suggesting that intracellular MT is an important adaptive mechanism decreasing CdC12 nephrotoxicity, and that a single injection of CdMT may not be a good model to study chronic Cd nephropathy; (10) genetic background of mouse strains, rather than constitutive MT levels, is a more important determinant for Cd-induced acute testicular injury. In addition to Cd detoxication, MT-transgenic and MT-null mice are also good models to determine other functions of MT. MT plays important roles in maintaining Zn homeostasis and protection against Zn toxicity. Knock-out of the MT gene also renders animals/cells more vulnerable to oxidative stress and DNA alkylating agent-induced toxicity. Therefore, the MT-transgenic and knock-out mouse models provide complementary approaches to those used previously, and have greatly increased our understanding of the role of MT in Cd toxicology, as well as other biological functions of MT.
通过使用金属硫蛋白-I（MT-I）转基因动物以及MT-I和-II基因敲除动物，MT在镉毒理学中的作用已变得更加清晰。我们已经表明：（1）MT转基因和基因敲除小鼠的组织MT蛋白水平发生了改变；（2）除了组织锌浓度有轻微改变外，MT转基因和基因敲除小鼠在其他所检测的解毒系统中似乎是正常的；（3）MT似乎并不抑制胃肠道对镉的吸收，也不影响镉在组织中的分布；（4）MT减少了肝脏中镉的清除；（5）MT可预防急性无机镉诱导的致死性和肝毒性，这种保护机制似乎是由于其将镉螯合在细胞质中的能力，从而减少了关键细胞器中的镉含量；（6）MT调节镉诱导的小鼠肝脏中原癌基因（c-jin）和肿瘤抑制基因（p53）的表达；（7）MT不能预防镉-金属硫蛋白（CdMT）诱导的急性肾损伤，而且锌对CdMT诱导的急性肾毒性的保护作用似乎不是通过MT介导的；（8）长期给予镉会导致MT基因敲除小鼠出现肾损伤，这表明镉诱导的肾毒性不一定是通过CdMT复合物介导的；（9）MT可预防慢性氯化镉肾病，这表明细胞内MT是降低氯化镉肾毒性的一种重要适应性机制，而且单次注射CdMT可能不是研究慢性镉肾病的良好模型；（10）小鼠品系的遗传背景，而非组成型MT水平，是镉诱导的急性睾丸损伤更重要的决定因素。除了镉解毒外，MT转基因和基因敲除小鼠也是确定MT其他功能的良好模型。MT在维持锌稳态以及预防锌毒性方面发挥着重要作用。MT基因的敲除也使动物/细胞更容易受到氧化应激和DNA烷化剂诱导的毒性影响。因此，MT转基因和基因敲除小鼠模型为先前使用的方法提供了互补的途径，并极大地增进了我们对MT在镉毒理学中的作用以及MT其他生物学功能的理解。
