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

UNLABELLED: 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. 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.

Pathogenic role of natural killer T and natural killer cells in acetaminophen-induced liver injury in mice is dependent on the presence of dimethyl sulfoxide.

UNLABELLED: Dimethyl sulfoxide (DMSO) is commonly used in biological studies to dissolve drugs and enzyme inhibitors with low solubility. Although DMSO is generally thought of as being relatively inert, it can induce biological effects that are often overlooked. An example that highlights this potential problem is found in a recent report demonstrating a pathogenic role for natural killer T (NKT) and natural killer (NK) cells in acetaminophen-induced liver injury (AILI) in C57Bl/6 mice in which DMSO was used to facilitate acetaminophen (APAP) dissolution. We report that NKT and NK cells do not play a pathologic role in AILI in C57Bl/6 mice in the absence of DMSO. Although AILI was significantly attenuated in mice depleted of NKT and NK cells prior to APAP treatment in the presence of DMSO, no such effect was observed when APAP was dissolved in saline. Because of this unexpected finding, the effects of DMSO on hepatic NKT and NK cells were subsequently investigated. When given alone, DMSO activated hepatic NKT and NK cells in vivo as evidenced by increased NKT cell numbers and higher intracellular levels of the cytotoxic effector molecules interferon-gamma (IFN-gamma) and granzyme B in both cell types. Similarly, when used as a solvent for APAP, DMSO again increased NKT cell numbers and induced IFN-gamma and granzyme B expression in both cell types. CONCLUSION: These data demonstrate a previously unappreciated effect of DMSO on hepatic NKT and NK cells, suggesting that DMSO should be used cautiously in experiments involving these cells.

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

Current evidence suggests that drug-induced liver disease can be caused by an allergic response (drug-induced allergic hepatitis, DIAH) induced by hepatic drug-protein adducts. The relatively low incidence of these reactions has led us to hypothesize that tolerogenic mechanisms prevent DIAH from occurring in most people. Here, we present evidence for the existence of one of these regulatory pathways. Following a hepatotoxic dose of acetaminophen in C57Bl/6 mice, lymphocyte loss that appeared to be due at least in part to apoptosis was noted in the spleen, thymus, and draining lymph nodes of the liver. There was no observable lymphocyte loss in the absence of hepatotoxicity. Acetaminophen-induced liver injury (AILI) also led to a functional suppression of the immune system as determined by the inhibition of a delayed-type hypersensitivity response to dinitrochlorobenzene. Further studies with adrenalectomized mice suggested a role for corticosterone in the depletion of lymphocytes following APAP-induced liver injury. In conclusion, these findings suggest that lymphocyte loss and immunosuppression following AILI may prevent subsequent occurrences of allergic hepatitis and possibly other forms of APAP-induced allergies induced by hepatic drug-protein adducts. Similar regulatory pathways may inhibit other hepatotoxic drugs from causing allergic reactions.