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

doi:10.1016/j.bbrc.2010.05.126

Biochemical and Biophysical Research Communications

Volume 397, Issue 3, 2 July 2010, Pages 453-458

https://doi.org/10.1016/j.bbrc.2010.05.126 Get rights and content

Abstract

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.

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

Abstract

Introduction

Section snippets

Mice and treatment

Results and discussion

Acknowledgments

J. Hepatol.

Gastroenterology

Hepatology

Toxicol. Appl. Pharmacol.

Arch. Biochem. Biophys.

Anal. Biochem.

J. Psychosom. Res.

Psychosomatics

J. Biol. Chem.

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

Ann. Intern. Med.

Hepatotoxicity: The Adverse Effects of Drugs and other Chemicals on the Liver

Drug-induced liver injury: insights from genetic studies

Pharmacogenomics

Impaired oxidation of debrisoquine in patients with perhexiline liver injury

Gut

Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review

JAMA

HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Nat. Genet.

Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity

Pharmacogenet. Genomics

Hypersensitivity reactions to drugs in acquired immunodeficiency syndrome

Postgrad. Med. J.

The drug hypersensitivity syndrome: what is the pathogenesis?

Arch. Dermatol.

Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus

Am. J. Respir. Crit. Care Med.

Cytokines and toxicity in acetaminophen overdose

J. Clin. Pharmacol.

Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease

Chem. Res. Toxicol.

Lymphocyte loss and immunosuppression following acetaminophen-induced hepatotoxicity in mice as a potential mechanism of tolerance

Chem. Res. Toxicol.