Primary rat hepatocyte toxicity 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 . A method of determining whether a compound induces at least one toxic effect on a tissue or cell, comprising:
 (a) preparing a gene expression profile of a tissue or cell sample exposed to said compound; and   (b) comparing the gene expression profile to a database comprising an adequate amount of the data or information of Tables 5A-5XX to determine whether the compound induces at least one toxic effect on the tissue or cell.   
     
     
         2 . A method of  claim 1 , wherein the gene expression profile prepared from the tissue or cell sample comprises the level of expression for at least one gene. 
     
     
         3 . A method of  claim 2 , wherein the level of expression is compared to a Tox Mean and/or Non-tox Mean value in Tables 5A-5XX. 
     
     
         4 . A method of  claim 3 , wherein the level of expression is normalized prior to comparison. 
     
     
         5 . A method of  claim 1 , wherein the database comprises substantially all of the data or information in Tables 5A-5XX. 
     
     
         6 . A method of predicting at least one toxic effect of a compound, comprising:
 (a) detecting the level of expression in a tissue or cell sample exposed to the compound of two or more genes from Tables 5A-5XX; wherein differential expression of the genes in Tables 5A-5XX is indicative of at least one toxic effect.   
     
     
         7 . A method of predicting the progression of a toxic effect of a compound, comprising:
 (a) detecting the level of expression in a tissue or cell sample exposed to the compound of two or more genes from Tables 5A-5XX; wherein differential expression of the genes in Tables 5A-5XX is indicative of toxicity progression.   
     
     
         8 . A method of predicting the hepatotoxicity of a compound, comprising:
 (a) detecting the level of expression in a tissue or cell sample exposed to the compound of two or more genes from Tables 5A-5XX; wherein differential expression of the genes in Tables 5A-5XX is indicative of hepatotoxicity.   
     
     
         9 . A method of identifying an agent that modulates the onset or progression of a toxic response, comprising:
 (a) exposing a cell to the agent and a known toxin; and   (b) detecting the expression level of two or more genes from Tables 5A-5XX; wherein differential expression of the genes in Tables 5A-5XX is indicative of toxicity.   
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 6 , wherein the expression levels of at least 3 genes are detected. 
     
     
         12 . The method of  claim 6 , wherein the expression levels of at least 5 genes are detected. 
     
     
         13 . The method of  claim 6 , wherein the expression levels of at least 10 genes are detected. 
     
     
         14 . The method of  claim 6 , wherein the expression levels of at least 50 genes are detected. 
     
     
         15 . The method of  claim 6 , wherein the expression levels of at least 100 genes are detected. 
     
     
         16 . The method of  claim 6 , wherein the expression levels of at least 500 genes are detected. 
     
     
         17 . A method of  claim 6 , wherein substantially all of the genes in Tables 5A-5XX are detected. 
     
     
         18 . (canceled) 
     
     
         19 . A method of  claim 6 , wherein the compound exposure is in vitro. 
     
     
         20 . A method of  claim 19 , wherein the cell sample comprises rat hepatocytes. 
     
     
         21 - 62 . (canceled)