Masson Mary Jane, Collins Lindsay A, Carpenter Leah D, Graf Mary L, Ryan Pauline M, Bourdi Mohammed, Pohl Lance R
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Biochem Biophys Res Commun. 2010 Jul 2;397(3):453-8. doi: 10.1016/j.bbrc.2010.05.126. Epub 2010 May 27.
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 (CCl(4))-induced liver injury, demonstrating the complexity of GC effects in different types of liver injury.
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.
我们之前报道过，对乙酰氨基酚（APAP）诱导的小鼠肝损伤（AILI）与糖皮质激素（GC）皮质酮血清水平升高有关。在本研究中，我们提供证据表明内源性GC在AILI中起病理作用。具体而言，用糖皮质激素受体（GCR）抑制剂RU486（米非司酮）预处理小鼠，可保护正常小鼠而非肾上腺切除小鼠免受AILI影响，而用合成GC地塞米松预处理则会加重AILI。RU486不影响全肝还原型谷胱甘肽（GSH）的消耗或APAP - 蛋白质加合物的形成。它对活性氧的形成、线粒体GSH或ATP的消耗也没有影响。虽然RU486预处理也能预防氟烷诱导的肝损伤，但它会加重刀豆蛋白A（ConA）和四氯化碳（CCl₄）诱导的肝损伤，表明GC在不同类型肝损伤中的作用具有复杂性。
这些结果表明，在某些情况下，GC水平升高可能是APAP和其他药物通过GCR调节的多种生物学过程导致肝损伤的一个先前未被认识到的危险因素。
