Genomic biomarkers for cardiotoxicity in rats as a sensitive tool in preclinical studies

Abstract

The development of safer drugs is a high priority for pharmaceutical companies. Among the various toxicities caused by drugs, cardiotoxicity is an important issue because of its lethality. In addition, cardiovascular toxicity leads to the attrition of many drug candidates in both preclinical and clinical phases. Although histopathological and blood chemistry examinations are the current gold standards for detecting cardiotoxicity in preclinical studies, the large number of withdrawals from clinical studies owing to safety problems indicate that a more sensitive tool is required. We recently identified 32 genes that were candidate genomic biomarkers for cardiotoxicity in rats. Based on their functions, the present study focused on 8 of these 32 genes (Spp1, Fhl1, Timp1, Serpine1, Bcat1, Lmcd1, Rnd1 and Tgfb2). Diagnostic accuracy for the genes was determined by a receiver-operating characteristic (ROC) analysis using more cardiotoxic and non-cardiotoxic compounds. In addition, an optimized support vector machine (SVM) model that was composed of Spp1 and Timp1 was newly constructed. This new multi-gene model exhibited a much higher diagnostic accuracy than that observed for plasma cardiac troponin I (cTnI), which is one of the most useful plasma biomarkers for cardiotoxicity detection. Furthermore, we determined that this multi-gene model could predict potential cardiotoxicity in rats in the absence of any cardiac histopathological lesions or elevations of plasma cTnI. Overall, this multi-gene model exhibited advantages over classic tools commonly used for cardiotoxicity evaluations in rats. Our current results suggest that application of the model could potentially lead to the production of safer drugs.

Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity

“…Chromosomal aberrations are mechanistically classified into structural aberrations and numerical aberrations. DNA damaging compounds-including DNA alkylating compounds, DNA cross-linking compounds, topoisomerase inhibitors, or anti-metabolites in DNA synthesis-induce Toxicogenomics is a powerful approach for elucidating mechanisms underlying toxicological phenotypic changes (Battershill, 2005;Chen et al, 2012;Heinloth et al, 2004;Uehara et al, 2011) and a useful strategy for identifying biomarker genes for individual toxicity endpoints, such as hepatotoxicity (Low et al, 2011), nephrotoxicity (Kondo et al, 2009;Minowa et al, 2012;Uehara et al, 2013), cardiac toxicity (Mori et al, 2010;Nishimura et al, 2013) and carcinogenicity (Rohrbeck et al, 2010;Uehara et al, 2008;Uehara et al, 2011). Important scientific breakthroughs have been achieved by applying toxicogenomics to genotoxic test.…”

Plasma miR‐208 as a useful biomarker for drug‐induced cardiotoxicity in rats

“…We have reported a multi-gene model for sensitive detection of cardiotoxicity in rats for use in preclinical studies (Nishimura et al, 2013). The multi-gene model showed superior performance compared with plasma cardiac troponin I (cTnI), one of the conventional biomarkers for cardiotoxicity.…”

Molecular biomarkers of phospholipidosis in rat blood and heart after amiodarone treatment

“…More than a few reasons justify the execution of the present study. These include (i) the need to better understand the molecular pathways involved in PLD occurrence in target tissues including the heart (Nioi et al ., ; Nonoyama and Fukuda, ); (ii) to discover early biomarkers helpful either to identify new therapeutic targets (Wang et al ., ) than predict the compound‐induced target organ toxicity (Nishimura et al ., ); and (iii) finally, to verify whether PBMCs may be considered as a surrogate of inaccessible target tissues such as the heart (Lee et al ., ). It should be emphasized that a certain number of papers about the effects of PLD‐inducing agents on gene expression signatures have already been published.…”

“…One of the major challenges facing pharmaceutical companies is determining potential toxicities early in the developmental process. Most published toxicogenomic data are mainly on the liver and kidney, owing to their fundamental role in xenobiotic metabolism and clearance (Dadarkar et al ., ; Nishimura et al ., ). Nonetheless, the accessibility of these and other target tissues is always difficult without sacrificing the animals and subjecting them to an invasive procedure.…”

“…Peripheral blood mononuclear cells gene expression profiling can be used as a surrogate tissue for cardiotoxicity, which is a serious safety problem impacting on the development of new drugs (Lee et al ., ; Nishimura et al ., ). The heart and blood cells are targets for CAD‐induced PLD (Horn et al ., ; Kannan et al ., ; Nonoyama and Fukuda, ), and there is a concrete need to identify early biomarkers for this change (Yudate et al ., ).…”