Differential hepatotoxicity induced by cadmium in Fischer 344 and Sprague-Dawley rats
Differential hepatotoxicity induced by cadmium in Fischer 344 and Sprague-Dawley rats
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DOI：
10.1093/toxsci/65.1.151
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发表时间：
2002-01-01
影响因子：
3.8
通讯作者：
Sipes, IG
中科院分区：
文献类型：
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作者：
Kuester, RK;Waalkes, MP;Sipes, IG
许多报告证明，Fischer 344(F344)大鼠比Spraogue-Dawley(SD)大鼠更容易受到化学性肝损伤的影响。镉(Cd Cl2)是一种不需要生物激活的肝毒物质，它被用来更好地定义导致F344和SD大鼠肝脏损伤差异的生物事件。氯化镉(3 mg/kg)对两种品系大鼠均有肝毒性，但血浆丙氨酸氨基转移酶(ALT)活性显示F344大鼠的肝损伤为F344大鼠的18倍。当分离的肝细胞与氯化镉体外孵育时，这种毒性的差异没有观察到，这表明其他类型的细胞在体内参与了镉诱导的肝毒性。事实上，F344大鼠肝内皮细胞(EC)的筛板受损程度高于SD大鼠。此外，抑制Kupffer细胞(KC)降低了两个菌株的肝毒性，表明这种细胞类型参与了氯化镉诱导的肝毒性的进展。此外，热休克蛋白72的合成增强在SD大鼠中出现得更早。肝脏金属硫蛋白(MT)是一种与镉耐受性相关的蛋白质，在SD大鼠中的最大水平更高。与F344大鼠相比，这些保护性因素可能通过减少KC的激活和随后导致肝损伤进展的炎症反应来限制CdCl2诱导的SD大鼠肝细胞损伤。
A number of reports document that Fischer 344 (F344) rats are more susceptible to chemically induced liver injury than Sprague-Dawley (SD) rats. Cadmium (CdCl2), a hepatotoxicant that does not require bioactivation, was used to better define the biological events that are responsible for the differences in liver injury between F344 and SD rats. CdCl2 (3 mg/kg) produced hepatotoxicity in both rat strains, but the hepatic injury was 18-fold greater in F344 rats as assessed by plasma alanine aminotransferase (ALT) activity. This difference in toxicity was not observed when isolated hepatocytes were incubated with CdCl2 in vitro, indicating that other cell types contribute to Cd-induced hepatotoxicity in vivo. Indeed, the sieve plates of hepatic endothelial cells (EC) in F344 rats were damaged to a greater degree than EC in SD rats. Additionally, Kupffer cell (KC) inhibition reduced hepatotoxicity in both strains, suggesting that this cell type is involved in the progression of CdCl2-induced hepatotoxicity. Moreover, enhanced synthesis of heat shock protein 72 occurred earlier in the SD rat. Maximal levels of hepatic metallothionein (MT), a protein associated with cadmium tolerance, were greater in SD rats. These protective factors may limit CdCl2-induced hepatocellular injury in SD compared with F344 rats by reducing KC activation and the subsequent inflammatory response that allows for the progression of hepatic injury.