Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice
Introduction
Drug-induced liver injury (DILI) is a serious health problem that accounts for over 50% of the cases of acute liver failure in the United States [1]. While the occurrence of DILI is quite high due to the estimated >1000 drugs that have been associated with liver injury [2], with the exception of APAP, the incidence for a particular drug is less than 1% [2], [3]. This low frequency, combined with insufficient knowledge of the underlying mechanisms, makes it impossible to predict who will be susceptible to DILI. Even in the case of APAP, where there is a clear relationship between overdose and liver failure, it is not entirely possible to predict susceptibility to liver injury [4]. As a result, there is considerable interest in identifying risk factors of DILI. To date, a number of potential predisposing factors have been associated with DILI in humans (reviewed in [5]), including gender [6], age [6], genetic polymorphisms in drug metabolizing enzymes [7], [8], [9], major histocompatibility complex [10], cytokines [11], and viral infections [12], [13], [14] as well as numerous other potential risk factors that have been identified in animal models of AILI [15], [16].
As a follow up to our recent observation that the severity of AILI in mice correlated with increased serum levels of corticosterone [17], we have now explored the possibility that corticosterone might also play a role in AILI. We found that pretreatment with the GCR inhibitor, RU486, protected mice from APAP- and halothane-induced liver injury, a surprising finding considering GC are generally thought to be useful for the treatment of immune-mediated DILI due to their immunosuppressive effects [18], [19], [20].
Section snippets
Mice and treatment
Eight week old male C57Bl/6J (stock# 000664) and female Balb/cJ mice (stock# 000651) were obtained from Jackson Laboratories (Bar Harbor, ME) and acclimatized at NIH facilities for 1 week. Experiments were conducted with the approval of the NHLBI Animal Use and Care Committee and animals received humane care according to the criteria outlined in the “Guide for the Care and Use of Laboratory Animals” published by the National Institutes of Health (NIH publication 86-23 revised 1985). For
Results and discussion
To investigate the role of corticosterone in AILI, mice were pretreated with RU486 or vehicle control 2 h prior to APAP treatment. RU486 pretreatment inhibited AILI at all time points up to 24 h, as determined by reduced serum ALT activity (Fig. 1A), a biomarker of liver injury, and histological evidence of diminished perivenous necrosis (Fig. 1B). Additional experiments were conducted to determine whether the protective effects of RU486 were related to its inhibitory actions on GCRs. RU486
Acknowledgments
This research was supported by the Intramural Research Program of the NIH and the NHLBI.
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