Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice.
Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice.
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DOI：
10.1016/j.bbrc.2010.05.126
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发表时间：
2010-07-02
影响因子：
3.1
通讯作者：
Pohl, Lance R.
中科院分区：
文献类型：
--
作者：
Masson, Mary Jane;Collins, Lindsay A.;Carpenter, Leah D.;Graf, Mary L.;Ryan, Pauline M.;Bourdi, Mohammed;Pohl, Lance R.
对乙酰氨基酚（APAP）诱导的小鼠肝损伤（AILI）与血清糖皮质激素（GC）、皮质酮（corticosterone）水平升高有关。在目前的研究中，我们提供的证据表明，内源性GC在AILI的病理作用。具体地说，用GC受体（GCR）抑制剂RU 486（米非司酮）预处理小鼠，保护正常但肾上腺切除小鼠免受AILI，而用地塞米松（一种合成GC）预处理则加重AILI。RU 486不影响全肝还原GSH的消耗或APAP-蛋白加合物的形成。它也没有影响活性氧的形成或线粒体GSH或ATP的耗竭。虽然RU 486预处理也防止氟烷诱导的肝损伤，但它加剧了刀豆球蛋白A（ConA）和四氯化碳（CCl 4）诱导的肝损伤，表明GC在不同类型的肝损伤中的作用的复杂性。结论：这些结果表明，在某些条件下，GC水平升高可能是APAP和其他药物通过GCR调节的各种生物过程引起肝损伤的一个以前未被认识到的风险因素。
We previously reported that acetaminophen (APAP)-induced liver injury (AILI) in mice is associated with a rise in serum levels of the glucocorticoid (GC), corticosterone. In the current study, we provide evidence that endogenous GC play a pathologic role in AILI. Specifically, pretreatment of mice with the GC receptor (GCR) inhibitor, RU486 (mifepristrone), protected normal but not adrenalectomized mice from AILI, while pretreatment with dexamethasone, a synthetic GC, exacerbated AILI. RU486 did not affect the depletion of whole liver reduced GSH or the formation of APAP-protein adducts. It also had no effects on the formation of reactive oxygen species or the depletion of mitochondrial GSH or ATP. While RU486 pretreatment also protected against halothane-induced liver injury, it exacerbated concanavalin A (ConA)- and carbon tetrachloride (CCl4)-induced liver injury, demonstrating the complexity of GC effects in different types of liver injury. Conclusion: These results suggest that under certain conditions, elevated levels of GC might represent a previously unappreciated risk factor for liver injury caused by APAP and other drugs through the diverse biological processes regulated by GCR.
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