List of metabolites from rat myocardium tissues in both MTX treated and untreated conditions

Cardiotoxicity is a well-established adverse effect of several drugs across multiple therapeutic indications. It is particularly prevalent following anticancer therapy. In order to evaluate the changes in metabolism associated with cardiotoxicity, we treated Wistar rats with a single high dose of methotrexate, and after five days, the animals were sacrificed. We then analyzed the cardiotoxicity parameters in serum and cardiac tissue with the goal of identifying a metabolic signature of cardiotoxicity using discovery-based metabolomics.

The results showed a total of 95 metabolites that were found to be significantly (p < 0.05) modulated: either up- or downregulated in the HDMTX-treated group when compared with the control group. Based on these metabolites, it was found via integrated pathway analysis that a majority of the metabolites were associated with many important cardiac tissue metabolic pathways, such as the malate aspartate shuttle, taurine and hypotaurine metabolism, betaine metabolism, spermidine and spermine biosynthesis, and homocysteine degradation. Among them, L-arginine, homocysteine, and betaine were significantly upregulated, suggesting their role in cardiac tissue injury. The metabolic signature of toxicity may offer a novel approach to the prediction of elevated betaine levels as the novel biomarker for cardiotoxic potential due to HDMTX cardiac toxicity.