Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice.
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.


CONCLUSIONS
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.
Masson
Mary Jane
MJ
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. massonm@nhlbi.nih.gov
Collins
Lindsay A
LA
Carpenter
Leah D
LD
Graf
Mary L
ML
Ryan
Pauline M
PM
Bourdi
Mohammed
M
Pohl
Lance R
LR
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D003345:Corticosterone / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013312:Stress, Physiological
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000082:Acetaminophen; D003907:Dexamethasone; D003345:Corticosterone