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Daunorubicin (DAUN) and doxorubicin (DOX) are used to treat a variety of cancers. The use of DAUN and DOX is hampered by the development of cardiotoxicity. Clinical evidence suggests that patients with leukemia and Down syndrome are at increased risk for anthracycline-related cardiotoxicity. Carbonyl reductases and aldo-keto reductases (AKRs) catalyze the reduction of DAUN and DOX into cardiotoxic C-13 alcohol metabolites. Anthracyclines also exert cardiotoxicity by triggering mitochondrial dysfunction. In recent studies, a collection of heart samples from donors with and without Down syndrome was used to investigate determinants for anthracycline-related cardiotoxicity including cardiac daunorubicin reductase activity (DA), carbonyl reductase/AKRs protein expression, mitochondrial DNA content (mtDNA), and AKR7A2 DNA methylation status. In this study, the available demographic, biochemical, genetic, and epigenetic data were integrated through classification and regression trees analysis with the aim of pinpointing the most relevant variables for the synthesis of cardiotoxic daunorubicinol (i.e., DA). Seventeen variables were considered as potential predictors. Leave-one-out-cross-validation was performed for model selection and to estimate the generalization error. The classification and regression trees analysis model and variable importance measures suggest that cardiac mtDNA content, mtDNA(4977) deletion frequency, and AKR7A2 protein content are the most important variables in determining DA., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The intracardiac synthesis of anthracycline alcohol metabolites by aldo-keto reductases (AKRs) contributes to the pathogenesis of anthracycline-related cardiotoxicity. AKR7A2 is the most abundant anthracycline reductase in hearts from donors with and without Down syndrome (DS), and its expression varies between individuals (≈tenfold). We investigated whether DNA methylation impacts AKR7A2 expression in hearts from donors with (n = 11) and without DS (n = 30). Linear models were used to test for associations between methylation status and cardiac AKR7A2 expression. In hearts from donors without DS, DNA methylation status at CpG site -865 correlated with AKR7A2 mRNA (Pearson's regression coefficient, r = -0.4051, P = 0.0264) and AKR7A2 protein expression (r = -0.5818, P = 0.0071). In heart tissue from donors with DS, DNA methylation status at CpG site -232 correlated with AKR7A2 protein expression (r = 0.8659, P = 0.0025). Multiple linear regression modeling revealed that methylation at several CpG sites is associated with the synthesis of cardiotoxic daunorubicinol. AKR7A2 methylation status in lymphoblastoid cell lines from donors with and without DS was examined to explore potential parallelisms between cardiac tissue and lymphoid cells. These results suggest that DNA methylation impacts AKR7A2 expression and the synthesis of cardiotoxic daunorubicinol.