Toxicogenomic Analysis of Cardiotoxicity in Rats

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 quantifi ed 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.

Phenotypic and genotypic assessment of concomitant drug‐induced toxic effects in liver, kidney and blood

“…Furthermore, by generating a toxicological ‘fingerprint’ of specific genes for a particular class of compounds, one can develop quick screening assay(s) for impending toxicity (Vass et al ., 2009). With this approach, measuring changes in specific gene expression can aid in prioritization of compounds before they are tested in more resource‐intensive and time‐consuming animal studies (Hirakawa et al ., 2008). Indeed, global evaluation of cellular and tissue transcriptomes has provided a powerful approach to interrogate perturbations induced by toxicants (Blomme and Warder, 2008).…”