Diquat- and acetaminophen-induced alterations of biliary efflux of iron in rats.
Diquat- and acetaminophen-induced alterations of biliary efflux of iron in rats.
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敌草快和对乙酰氨基酚诱导大鼠胆汁铁流出的改变。
DOI：
10.1016/0006-2952(94)90084-1
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发表时间：
1994
影响因子：
5.8
通讯作者：
Smith,CV
中科院分区：
文献类型：
--
作者：
Benzick,AE;Reddy,SL;Gupta,S;Rogers,LK;Smith,CV
研究敌草快对大鼠非血红素铁胆汁外排的影响，作为检查敌草快代谢对肝细胞铁代谢的可能影响以及铁代谢改变与急性肝坏死发生的关系的一种手段。对雄性Fischer-344大鼠给予肝毒性剂量（0.1 mol/kg）敌草快，使胆汁铁浓度从6 μM增加到15 μM以上。然而，在暴露于敌草快后的第一个60分钟内没有观察到铁的胆汁流出增加，尽管胆汁中谷胱甘肽二硫化物浓度迅速增加，在40分钟内增加最大。铁的胆汁流出没有改变敌草快在Sprague-Dawley大鼠，这是抵抗肝坏死，敌草快，尽管在这些动物中观察到显着的氧化应激反应。相反，肝毒性剂量的对乙酰氨基酚（1500 mg/kg）导致胆汁铁流出量显著减少。对乙酰氨基酚引起的胆汁铁快速减少和敌草快诱导的铁外排延迟表明，部分胆汁铁可能以可逆形成的GS-Fe 2+螯合物的形式排泄，敌草快可通过谷胱甘肽二硫化物（GSSG）抑制外排，对乙酰氨基酚给药动物可通过3-（谷胱甘肽-S-基）对乙酰氨基酚（GS-AAP）抑制外排。然而，50-200 mg/kg剂量的对乙酰氨基酚对胆汁铁排泄几乎没有影响，尽管产生的胆汁GS-AAP结合物浓度几乎是6μM铁浓度的1000倍，这似乎不支持GS-Fe 2+螯合物排泄的假设。这些数据表明敌草快对Fischer-344大鼠肝脏铁代谢有显著影响，而敌草快处理的Sprague-Dawley大鼠没有类似的反应，表明这种铁再分布对活性氧介导的体内细胞损伤可能具有重要意义。
The effects of diquat on the biliary efflux of nonheme iron in rats were studied as a means of examining the possible effects of diquat metabolism on hepatocellular iron metabolism and the association of altered iron metabolism with the initiation of acute hepatic necrosis. Administration of hepatotoxic doses (0.1 mol/kg) of diquat to male Fischer-344 rats increased biliary iron concentrations from 6 μM to more than 15 μM. However, increases in biliary efflux of iron were not observed during the first 60 min following exposure to diquat, despite the rapid increases in biliary glutathione disulfide concentrations, which increased maximally within 40 min. Biliary efflux of iron was not altered by diquat in Sprague-Dawley rats, which are resistant to hepatic necrosis in response to diquat, despite the marked oxidant stress responses observed in these animals. Conversely, hepatotoxic doses of acetaminophen (1500 mg/kg) caused significantdecreasesin biliary iron efflux. The rapid decreases in biliary iron caused by acetaminophen and the delay in diquat-induced iron efflux suggested the possibility that some fraction of the biliary iron was being excreted as reversibly formed GS-Fe2+chelates, with inhibition of export by glutathione disulfide (GSSG) in the case of diquat, or by 3-(glutathion-S-yl)acetaminophen (GS-AAP) in the case of the acetaminophen-treated animals. However, 50–200 mg/kg doses of acetaminophen showed little effect on biliary iron excretion despite producing biliary GS-AAP conjugate concentrations almost 1000 times the 6μM concentrations of iron, which would not appear to support the hypothesis of excretion of GS-Fe2+chelates. The data demonstrate a significant effect of diquat on hepatic iron metabolism in Fischer-344 rats, and the possible importance of this iron redistribution to reactive oxygen-mediated cell damagein vivois indicated by the absence of similar responses in diquat-treated Sprague-Dawley rats.
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