Molecular toxicology modeling

Abstract

The present invention is based on the elucidation of the global changes in gene expression and the identification of toxicity markers in tissues or cells exposed to a known toxin. The genes may be used as toxicity markers in drug screening and toxicity assays. The invention includes a database of genes characterized by toxin-induced differential expression that is designed for use with microarrays and other solid-phase probes.

1 - 58 . (canceled) 
     
     
         59 . A method for classifying a test compound as a human hepatotoxin, comprising:
 (a) preparing a gene expression profile by hybridizing nucleic acids to oligonucleotide probes, the gene expression profile containing the differential expression levels for at least 100 genes in rat liver tissue or rat liver cells upon exposure to the test compound, wherein said at least 100 genes are listed in Table 1;   (b) comparing the gene expression profile to a plurality of hepatotoxicity models, each hepatotoxicity model comprising:
 the differential expression levels for at least 10 of said at least 100 genes in rat liver tissue or rat liver cells upon exposure to a hepatotoxin independently selected from acetominophen, acyclovir, ANIT, AY-25329, bicalutamide, carbon tetrachloride, clofibrate, cyproterone acetate, diclofenac, diflunisal, dioxin, estradiol, hydrazine, indomethacin, LPS, phenobarbitol, tacrine, valproate, WY-14643, and zileuton; and 
   (c) scoring the comparisons to classify the test compound as a human hepatotoxin.   
     
     
         60 . The method of  claim 59 , wherein the test compound is classified as inducing one or more of hepatitis, liver necrosis, cholestasis, tumor formation, protein adduct formation, liver enlargement, and fatty liver. 
     
     
         61 . The method of  claim 59 , wherein the test compound is classified as a non-hepatotoxin. 
     
     
         62 . The method of  claim 59 , wherein each hepatotoxicity model comprises the differential gene expression levels for at least 25 genes. 
     
     
         63 . The method of  claim 59 , wherein each hepatotoxicity model comprises the differential gene expression levels for at least 50 genes. 
     
     
         64 . The method of  claim 59 , wherein the gene expression profile is normalized for hybridization conditions, label intensity, and reading efficiency prior to comparison. 
     
     
         65 . The method of  claim 59 , wherein each hepatotoxicity model comprises gene expression information from one of Tables 3-3DD. 
     
     
         66 . The method of  claim 59 , wherein the comparison is scored by determining whether the test compound induces a change in expression of the at least 10 genes in the same direction as the hepatotoxin. 
     
     
         67 . The method of  claim 59 , wherein at least one model is a general hepatotoxicity model. 
     
     
         68 . The method of  claim 59 , wherein the rat liver tissue or rat liver cells were exposed to the test compound for about 1 to about 48 hours.