Metallothionein-null mice are more sensitive than wild-type mice to liver injury induced by repeated exposure to cadmium
Metallothionein-null mice are more sensitive than wild-type mice to liver injury induced by repeated exposure to cadmium
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DOI：
10.1093/toxsci/55.1.223
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发表时间：
2000-05-01
影响因子：
3.8
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Habeebu, SS;Liu, J;Klaassen, CD
肝脏是镉急性和慢性暴露的主要靶器官。金属硫蛋白（MT）是一种富含半胱氨酸的低分子量金属结合蛋白，在镉致急性肝损伤中起重要的保护作用。本研究探讨了MT在镉重复暴露引起的肝损伤中的作用。野生型和MT-I/II基因敲除（MT I/II-null）小鼠皮下注射范围广泛的氯化镉剂量，6次/周，长达10周，他们的肝脏镉含量，肝脏MT浓度，和肝损伤进行了检查。重复给药氯化镉产生急性和非特异性慢性炎症的实质和门静脉束和周围的中央静脉。较高剂量在肝实质中产生肉芽肿性炎症和增生性结节。反复镉暴露后，肝脏细胞凋亡和有丝分裂同时发生，而坏死是轻微的。结果，未观察到血清酶水平显著升高。在野生型小鼠中，肝脏镉浓度以剂量和时间依赖性方式增加，达到400微克/克肝脏，沿着肝脏MT浓度增加150倍，后者达到1200微克/克肝脏。相反，在MT I/II-null小鼠，肝脏镉浓度约为10微克/克肝脏。尽管较低的积累，镉在肝脏中的MT I/II-null小鼠，镉的最大耐受剂量是八分之一，低于野生型小鼠在10周，和肝损伤更明显的MT I/II-null小鼠，肝/体重比和组织病理学分析的增加证明。总之，这些数据表明：（1）非特异性慢性炎症，肉芽肿性炎症，细胞凋亡，肝细胞再生，并推测，癌前增生结节是由重复镉暴露引起的肝损伤的主要特征，和（2）细胞内MT是一个重要的蛋白质保护这种镉诱导的肝损伤。
Liver is a major target organ of cadmium (Cd) toxicity following acute and chronic exposure. Metallothionein (MT), a low-molecular-weight, cysteine-rich, metal-binding protein has been shown to play an important role in protection against acute Cd-induced liver injury. This study investigates the role of MT in liver injury induced by repeated exposure to Cd. Wild-type and MT-I/II knockout (MT I/II-null) mice were injected sc with a wide range of CdCl2 doses, 6 times/week, for up to 10 weeks, and their hepatic Cd content, hepatic MT concentration, and liver injury were examined. Repeated administration of CdCl2 produced acute and nonspecific chronic inflammation in the parenchyma and portal tracts and around central veins. Higher doses produced granulomatous inflammation and proliferating nodules in liver parenchyma. Apoptosis and mitosis occurred concomitantly in liver following repeated Cd exposure, whereas necrosis was mild. As a result, significant elevation of serum enzyme levels was not observed. In wild-type mice, hepatic Cd concentration increased in a dose- and time-dependent manner, reaching 400 mu g/g liver, along with 150-fold increases in hepatic MT concentrations, the latter reaching 1200 mu g/g liver. In contrast, in MT I/II-null mice, hepatic Cd concentrations were about 10 mu g/g liver. Despite the lower accumulation of Cd in livers of MT I/II-null mice, the maximum tolerated dose of Cd was one-eighth lower than that for wild-type mice at 10 weeks, and liver injury was more pronounced in the MT I/II-null mice, as evidenced by increases in liver/body weight ratios and histopathological analyses. In conclusion, these data indicate that (1) nonspecific chronic inflammation, granulomatous inflammation, apoptosis, liver cell regeneration, and presumably, preneoplastic proliferating nodules are major features of liver injury induced by repeated Cd exposure, and (2) intracellular MT is an important protein protecting against this Cd-induced Liver injury.