The use of anthracyclines for cancer chemotherapy is associated with the development of cardiotoxicity in some patients. The pathogenesis of anthracycline-related cardiotoxicity is mediated in part by the intracardiac synthesis of cardiotoxic alcohol metabolites (e.g., daunorubicinol). Anthracycline alcohol metabolites are synthesized by polymorphic carbonyl reductases (CBRs) and aldo-keto reductases (AKRs). Our research has contributed to: 1) identifying variants in CBR genes that impact the pharmacodynamics of anthracyclines, 2) identifying transcription factors and microRNAs that regulate the expression of CBRs, 3) documenting the extent of interindividual variability in the expression and activity of specific AKRs and CBRs in liver and heart, key organs for the pharmacodynamics of anthracyclines, and 4) defining the contribution of genetic polymorphisms in CBRs to the risk for anthracycline-related cardiotoxicity in survivors of pediatric cancers. Our recent findings indicate that: 1) DNA methylation status impacts cardiac expression of AKR7A2, and 2) protein levels of CBR1, AKR1A1, and AKR7A2, which are important determinants for the synthesis of cardiotoxic anthracycline alcohol metabolites in heart. Nonetheless, 30% to 50% of the variance in intracardiac daunorubicinol synthesis rates remains unexplained by current linear models based on group averages, which are insensitive to variation between individual CBRs/AKRs expression profiles and do not incorporate functional genetic and epigenetic factors. These fundamental limitations hamper the development of predictive tools for identifying patients likely to develop anthracycline-related cardiotoxicity. Thus, studies in Aim 1 will determine whether DNA methylation status in CBR1, CBR3, AKR1A1, AKR1C3, and AKR7A2 genes impacts gene expression and synthesis of cardiotoxic metabolites in heart and liver. In Aim 2, we will develop novel quantitative methods to predict the synthesis of anthracycline metabolites in heart and liver, and in paired peripheral blood lymphocytes (PBL). These methods will integrate quantitative genetic, epigenetic, and phenotypic data for the CBRs/AKRs involved in the metabolism of anthracyclines with the aim of defining specific expression profiles that result in outlier values for the synthesis of cardiotoxic metabolites. Translational studies i Aim 3 will determine whether functional genetic variants in the CBRs and AKRs are associated with changes in 3 measurements of cardiotoxicity obtained by sensitive tissue Doppler strain echocardiography: 1) left ventricular ejection fraction, 2) longitudinal strain, and 3) radial stran, in 130 breast cancer patients undergoing treatment with doxorubicin. In parallel, we will determine whether doxorubicinol maximal synthesis rates in PBL are associated with echocardiographic changes indicative of early cardiotoxicity. The tools arising from this research can potentially be incorporated into comprehensive clinical algorithms with the aim of identifying patients at risk for anthracycline-related cardiotoxicity.