Mechanisms Of Drug-induced Toxicities

Heart, Lung, And Blood Institute

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Abstract

We have continued our studies of the molecular basis of drug-induced liver disease (DILD), which is a rare but often life-threatening toxicity. It is the major cause of acute liver failure and a principal reason drugs are withdrawn from clinical use. We have hypothesized that the idiosyncratic nature of this disease is due in part to a deficiency in hepatoprotective factors. This idea has been explored in the following ways this year: [unreadable] [unreadable] [unreadable] 1. Last year we reported that endogenous IL-13 protected mice from acetaminophen-induced liver disease (AILD), at least in part, by down-regulating several proinflammatory cytokines and chemokines. This year we have found with the use of several neutralizing antibodies that the increased susceptibility of IL-13 knockout mice to AILD is due to a combination of several factors including interferon gamma, NK(T) cells, and neutrophils. It is possible that IL-13 also protects humans from not only AILD, but also liver diseaese caused by other drugs.[unreadable] [unreadable] 2. Current evidence indicates that DILD is often caused by an allergic response (drug-induced allergic hepatitis, DIAH) induced by hepatic drug-protein adducts. The low incidence of DIAH and inability to reproduce it in animals suggests that tolerogenic mechanisms may prevent DIAH from occurring in most people and animals. In this regard, last year we discovered that hepatotoxic doses of acetaminophen (APAP) were associated with marked losses of T cells and/or B cells cells in the thymus, spleen, and hepatic lymph nodes of mice as well as depression of the adaptive immune system. This year we have found that adrenalectomized mice are resistant to these effects, suggesting that stress and endogenous corticosteroids may decrease susceptibility to DIAH in both animals and humans. [unreadable] [unreadable] 3. This year we have discovered that endogenous IL-4 also protects mice form AILD. Based upon multiplex analysis of serum proteins from wild-type and IL-4 knockout mice following hepatotoxic doses of APAP, it appears that IL-4 protects mice from AILD, at least in part, by downreguling several proinflammatory cytokines.