Mechanism of manganese-induced tolerance to cadmium lethality and hepatotoxicity.
Mechanism of manganese-induced tolerance to cadmium lethality and hepatotoxicity.
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锰诱导的镉致死性和肝毒性耐受机制。
DOI：
10.1016/0006-2952(85)90673-2
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发表时间：
1985
影响因子：
5.8
通讯作者：
Klaassen,CD
中科院分区：
文献类型：
--
作者：
Goering,PL;Klaassen,CD
已知用Mn 2+预处理产生对Cd 2+诱导的致死性的耐受性。本研究旨在探讨锰预处理对镉诱导的致死性和肝毒性的耐受机制。大鼠静脉注射36 μmoles Cd 2 +/kg，在10-20小时内死亡，而用Mn 2+（250 μ mol/kg，s.c.，48和24小时前镉+挑战）死亡。Cd 2+处理10小时后，对照组大鼠血浆天门冬氨酸氨基转移酶和山梨醇脱氢酶活性明显升高，肝脏出现广泛的组织病理学病变，但Mn 2+预处理组大鼠则无明显病变。为了探讨这种耐受的机制，在对照组和Mn ~（2+）预处理的大鼠中，测定了Cd ~（2+）在14个器官中的分布和在6个器官中的亚细胞分布。激发后2小时（31 μ mol Cd 2 +/kg，静脉注射，0.75μ Ci 109 Cd ~（2+）/μmole Cd ~（2+），Mn ~（2+）预处理后，Cd ~（2+）在肝脏中的分布明显增加，而在其它组织中的分布则减少。Mn ~（2+）预处理也导致Cd ~（2+）在肝细胞亚细胞中分布的显著差异，Cd ~（2+）更多地存在于细胞质中，而较少与细胞器结合。凝胶过滤层析表明，大多数胞质镉2+结合到一个低分子量的蛋白。这种蛋白质的分离和部分表征表明，它是相同的金属硫蛋白（MT），它有一个类似的相对洗脱凝胶过滤层析后，在280 nm处有低吸光度，分离成两个同工蛋白后，通过DEAEA-25阴离子交换层析，具有相同的流动性后，非变性聚丙烯酰胺凝胶电泳镉+诱导的金属硫蛋白。这些数据表明，Mn 2+预处理降低Cd 2+诱导的肝毒性，通过改变肝脏亚细胞分布的Cd 2+与更多的Cd 2+结合MT在胞质溶胶中。这种降低的肝毒性可能是负责耐受镉+诱导的致死性。
Pretreatment with Mn2+is known to produce tolerance to Cd2+-induced lethality. This study was designed to determine the mechanism of tolerance to Cd2+-induced lethality and hepatotoxicity following Mn2+pretreatment. Rats given 36 μmoles Cd2+/kg, i.v., died within 10–20 hr while only one of nine rats pretreated with Mn2+(250 μmoles/kg, s.c., 48 and 24 hr prior to Cd2+challenge) died. Ten hours after Cd2+, plasma aspartate aminotransferase and sorbitol dehydrogenase activities were elevated markedly, and extensive histopathologic lesions of the liver were evident in control rats but not in Mn2+- pretreated rats. To examine the mechanism of this tolerance, distribution of Cd2+to fourteen organs and the subcellular distribution in six organs were determined in control and Mn2+-pretreated rats. Two hours after challenge (31 μmoles Cd2+/kg, i.v., 0.75 μCi109Cd2+/μmole Cd2+), the distribution of Cd2+to liver markedly increased after Mn2+pretreatment with concomitant decreases in other tissues. Mn2+pretreatment also resulted in a marked difference in the hepatic subcellular distribution of Cd2+with more present in cytosol and less associated with organelles. Gel-filtration chromatography indicated that most cytosolic Cd2+was bound to a low molecular weight protein. Isolation and partial characterization of this protein suggest that it is identical to metallothionein (MT); it had a similar relative elution following gel-filtration chromatography, had low absorbance at 280 nm and, after separation into two isoproteins by DEAE A-25 anion exchange chromatography, had the same mobility after electrophoresis on non-denaturing polyacrylamide gels as Cd2+-induced metallothioneins. These data suggest that Mn2+pretreatment reduces Cd2+-induced hepatotoxicity by altering the hepatic subcellular distribution of Cd2+with more Cd2+binding to MT in the cytosol. This decreased hepatotoxicity is probably responsible for tolerance to Cd2+-induced lethality.