Toxicometabolomics-Based Cardiotoxicity Evaluation of Thiazolidinedione Exposure in Human-Derived Cardiomyocytes.

Abstract

Abstract Introduction Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. Objective Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. Methods The present investigation included an untargeted liquid chromatography–mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. Results Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. The results also highlighted changes in polyamines (spermine and spermidine) and amino acid levels (L-tyrosine and valine), indicating phenotypic alterations in cardiac tissue (hypertrophy), which represents another characteristic of cardiotoxicity and a potential associated mechanism. In addition, this comprehensive study identified two groupings – (i) valine and creatine, and (ii) L-tryptophan and L-methionine – that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. Conclusion These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences.