Gadolinium chloride pretreatment prevents cadmium chloride-induced liver damage in both wild-type and MT-null mice
Gadolinium chloride pretreatment prevents cadmium chloride-induced liver damage in both wild-type and MT-null mice
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DOI：
10.1006/taap.2002.9385
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发表时间：
2002-05-01
影响因子：
3.8
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Harstad, EB;Klaassen, CD
重金属镉(Cd)急性给药可引起肝脏毒性。库普弗细胞是肝脏中的巨噬细胞，在镉诱导的肝毒性中起一定作用。GdCl3可能通过抑制Kupffer细胞而抑制Cd诱导的肝毒性。然而，GdCl3也诱导Cd结合蛋白金属硫蛋白(NIT)。因此，本研究旨在确定GdCl3是否通过诱导MT来预防Cd所致的肝毒性。给野生型(WT)小鼠注射生理盐水或GdCl3 10、30、60 mg/kg后24 h，检测肝脏NIT和Kupffer细胞计数。GdCl3以剂量依赖的方式诱导MT，但不影响非蛋白巯基含量。所有受试剂量的GdCl3都能有效地清除肝脏中的Kupffer细胞。为了观察GdCl3的保肝作用，WT和MT缺陷型小鼠在肝毒性剂量Cd(2.5 mg Cd/kg)前24 h分别给予生理盐水、10 mg、30 mg和60 mg GdCl3。16h后取出血液和肝脏，分析肝脏毒性以及NIT、CD和Kupffer细胞含量。给予30或60 mg/kg GdCl3的WT和MT缺失型小鼠的肝毒性均有所减轻，表明GdCl3的保肝作用不需要MT的诱导。GdCl3对肝脏Cd含量无明显影响，表明GdCl3对Cd在肝脏中的分布没有负面影响。Kupffer细胞在所有三种剂量的GdCl3中都被耗尽，而只有在30和60 mg GdCl3/kg的剂量下才能观察到肝保护作用。这并不排除Kupffer细胞在Cd诱导的肝毒性机制中的作用，但它确实表明GdCl3除了消耗Kupffer细胞外，还具有保护肝脏的作用。综上所述，这些数据基本上排除了NIT诱导，并降低了Kupffer细胞作为GdCl3诱导的保护Cd诱导的肝毒性的机制的重要性。(C)2002年埃尔塞维尔科学公司(美国)。
The heavy metal cadmium (Cd) causes hepatotoxicity upon acute administration. Kupffer cells, the resident macrophages of the liver, have been suggested to play a role in Cd-induced hepatotoxicity. Gadolinium chloride (GdCl3) may prevent Cd-induced hepatotoxicity by suppressing Kupffer cells. However, GdCl3 also induces the Cd-binding protein, metallothionein (NIT). Therefore, this study was conducted to determine whether GdCl3 prevents Cd-induced hepatotoxicity via the induction of MT. Hepatic NIT and Kupffer cell counts were analyzed 24 h after wild-type (WT) mice were administered saline or 10, 30, or 60 mg GdCl3/kg. GdCl3 induced MT in a dose-dependent manner without affecting nonprotein sulfhydryl content. All examined doses of GdCl3 were effective at eliminating Kupffer cells from the liver. To examine the hepatoprotective effects of GdCl3, WT and MT-null mice were pretreated with saline or 10, 30, or 60 mg GdCl3 24 h prior to a hepatotoxic dose of Cd (2.5 mg Cd/kg). Blood and livers were removed 16 h later and analyzed for hepatotoxicity as well as NIT, Cd, and Kupffer cell content. Hepatotoxicity was alleviated in both WT and MT-null mice that were pretreated with 30 or 60 mg GdCl3/kg, indicating that MT induction is not required for the hepatoprotective effects of GdCl3. Hepatic Cd content was not decreased by GdCl3, demonstrating that GdCl3 does not negatively affect Cd distribution to the liver. Kupffer cells were depleted at all three doses of GdCl3, whereas hepatoprotection was only observed at doses of 30 and 60 mg GdCl3/kg. This does not rule out Kupffer cells in the mechanism of Cd-induced hepatotoxicity, but it does suggest that GdCl3 exerts hepatoprotective effects on the liver aside from depleting Kupffer cells. In summary, these data substantially rule out NIT induction and decrease the importance of Kupffer cells as mechanisms of GdCl3-induced protection from Cd-induced hepatotoxicity. (C) 2002 Elsevier Science (USA).