Idiosyncratic, adverse drug reactions (ADRs) have serious health and economic consequences, yet they are not identified in preclinical testing due to a lack of predictive models. We have developed an animal model that reproduces idiosyncratic liver injury. The model involves treatment of rats with a nontoxic dose of lipopolysaccharide (LPS) to induce mild inflammation followed by treatment with a nontoxic dose of drug. Using this model with two drugs in different pharmacological classes, hepatic gene expression near the onset of injury distinguishes drugs associated with idiosyncratic liver injury in humans from drugs with similar structures that do not have this liability. The long term goal of this research is to evaluate the usefulness of changes in hepatic gene expression in animal models of drug-inflammation interaction as a preclinical predictor of the propensity of drugs to cause idiosyncratic hepatotoxicity in humans. To test the hypothesis that global, hepatic gene expression changes in animal models of inflammation-drug interactions can be used to predict the propensity of drugs to cause human, idiosyncratic liver injury, rats will be cotreated with LPS and one of several drugs (at doses that alone are not hepatotoxic), and microarray analysis of gene expression will be performed on livers.
In Specific Aim 1, hepatic gene expression will be analyzed for treatment-related changes. Drugs known to produce idiosyncratic liver injury in people and drugs that are in the same pharmacological classes but are not associated with idiosyncrasy will serve as a """"""""training set"""""""" in this Aim.
In Aim 2, the microarray data will be analyzed for patterns of expression unique to the drug-inflammation interactions that are associated with idiosyncrasy-producing drugs, and the expression data will be probed for specific genes or sets of genes that determine these unique patterns.
In Aim 3, additional drugs will be used as a """"""""validation set"""""""" to evaluate the usefulness of the patterns and genes identified in Aims 1 and 2. The immediate product of these studies will be an animal model of drug-inflammation interaction for which a set of genes has been identified that predicts the propensity for a drug to cause idiosyncratic liver injury in people. If successful, these studies will provide models with which to identify preclinically those drugs that could cause this type of liver damage in people. The relevance of this research to public health lies in the potential to prevent the occurrence of """"""""unpredictable"""""""", drug-induced liver damage.
