Brad Hirakawa^1,2, Bart A. Jessen², Oscar Illanes², Ann de Peyster¹, Thomas McDermott² and Gregory J. Stevens²

¹Graduate School of Public Health, Hardy Tower 119, 5500 Campanile Drive, San Diego State University, San Diego, California 92182; and ²Pfizer Global Research and Development, 10578 Science Center Drive, San Diego, California 92121.

Abstract

Evidence of cardiotoxicity in the preclinical testing of drugs will often lead to compound attrition. The standard method for identifying cardiotoxic compounds involves histopathological analysis of tissue sections, a resource intensive process. In an effort to reduce attrition and capture safety endpoints early within the drug discovery paradigm, a more rapid assessment of target organ effects is desired. Here we describe the results of a preliminary study in which a group of common genes were affected by in vivo exposure to compounds known to cause dose-dependant cardiotoxicity. Adult male Sprague-Dawley rats were treated intraperitoneally with a single dose of digoxin (20 mg/kg), doxorubicin (30 mg/kg), isoproterenol (70 mg/kg), lipopolysaccharide (10 mg/kg) or carbon tetrachloride (800 mg/kg) and euthanized either 6 or 24 hours post-dose. Digoxin, doxorubicin, isoproterenol, and lipopolysaccharide were chosen for this study based on their diverse mechanisms of cardiotoxicity. Carbon tetrachloride, a known liver toxicant, was chosen as a non-cardiotoxic negative control. Genes commonly affected by all four cardiotoxic compounds were grouped together as a list of potential biomarkers. Gene expression changes were subsequently quantified using quantitative PCR. These genes were compared to those affected by novel experimental compounds previously shown to cause cardiotoxicity in rats. These compounds also affected over half of the genes on the biomarker list, whereas the non-cardiotoxic control compound did not affect any genes on the biomarkers list. These data indicate that measuring changes in gene expression could aid in the prioritization of compounds before they are tested in more resource intensive studies.