Mechanisms Of Drug-induced Toxicities

National Heart, Lung, And Blood Institute

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Abstract

ANNUAL REPORT FOR 2009 1. This year we confirmed that IL-4 protects mice from AILI by increasing the synthesis of gamma-glutamylcysteinyl ligase (GCL), the rate determining step in the synthesis of the cytoprotective molecule glutathione. This was done by administering IL-4 to mice made deficient in this cytokine and showing that IL-4 treatment protected IL-4 deficient mice from severe AILI by increasing hepatic levels of GCL and glutathione. 2. This year we provide evidence suggesting that halothane-induced liver injury is caused at least in part by enhancing ER stress, which results in protein synthesis inhibition and rapid turnover of several antioxidant proteins that protect cells from injury. 3. C57BL/6 inbred mouse strain is one of the most widely used animals for research models. However, their popularity has led to the creation of several C57BL/6 mice substrains maintained within and among different vendors. In this regard, major discrepancies between C57BL/6 mice substrains have been shown in several areas of research including behavioral studies, diabetes, cancer and oxidative stress, among others. This year we have provided evidence describing similar problems in the field of toxicology. When a hepatotoxic dose of acetaminophen (APAP) was administered to substrains of C57BL/6 mice from 4 different vendors (Taconic Farms, Charles River, Harlan and The Jackson Laboratories), significant differences were found in their susceptibility to liver injury and survival. Comparing APAP bioactivation of C57BL/6J (The Jackson Laboratory;the least susceptible substrain) with C57BL/6Tac (Taconic Farms;one of the most susceptible substrains), we found by immunoblot analysis a reduced level of mitochondrial APAP protein-adducts in C57BL/6J mice compared to C57BL/6Tac that was correlated with mitochondrial levels of CYP2E1. Moreover, APAP treatment caused less mitochondrial glutathione (GSH) depletion in C57BL/6J mice compared to C57BL/6Tac. Interestingly, the levels of APAP protein-adducts and GSH in whole liver homogenates did not differ segnificantly between the two substrains. Overall, these findings suggest, for the first time, that susceptibility differences exist between different C57BL/6 mice substrains in APAP-induced liver injury model and possibly other forms of injury. It also stresses that researchers should carefully consider the appropriate C57BL/6 mice control when using genetically engineered mice on a C57BL/6 background, not only for toxicological research, but also for other biomedical studies.