periplocin and Cardiotoxicity

Periplocin, as one of the components of cardiac glycosides in Cortex periplocae, exhibited cardiotonic effects. Orally ingesting periplocin in high doses or over prolonged periods would cause serious adverse reactions, especially cardiotoxicity, which limits the applications of periplocin in clinical therapy. It has been reported that Panax notoginseng saponins could be used in compatibility with periplocin to reduce the cardiotoxicity of periplocin. To clarify the mechanisms of periplocin-induced cardiotoxicity and compatibility-pairing in reducing cardiotoxicity, the gas chromatography-mass spectrometry method was used to detect and analyze the metabolic profiles of rat plasma and urine samples after oral administration of periplocin, Panax notoginseng saponins, and the different compatibility ratios of periplocin and Panax notoginseng saponins. The multivariate statistical analysis method was used to screen and identify the biomarkers. A total of 49 potential biomarkers (28 in plasma and 21 in urine) associated with periplocin-induced cardiotoxicity were identified. Seven pathways were found through metabolomic pathway analysis. Moreover, the levels of 42 biomarkers (22 in plasma and 20 in urine) were close to normal after compatibility pairing. By analyzing the relative metabolic pathways, Panax notoginseng saponins could effectively reduce the cardiotoxicity of periplocin by affecting the tricarboxylic acid cycle, energy metabolism, and arachidonic acid metabolism.

Topics: Animals; Cardiotoxicity; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Gas Chromatography-Mass Spectrometry; Metabolomics; Panax notoginseng; Plant Extracts; Rats; Saponins; Tandem Mass Spectrometry

Corex Periplocae (the root of Periploca sepium Bge) has been widely used in clinics. Periplocin, as one of the components of cardiac glycosides in Corex Periplocae, easily triggers cardiotoxicity when used improperly. To evaluate the toxicity of Periplocin, we used UPLC-Q-TOF/MS to investigate metabolic profiles on neonatal rat cardiomyocytes exposed to high and low doses of Periplocin (0.2 mmol/L, 0.4 mmol/L). Finally, we identified 11 biomarkers associated with toxicity through multivariate statistical analysis. A "supervised" Support Vector Machine (SVM) study was used to optimize and verify the reliability of these biomarkers. In these biomarkers, all biomarkers, including carnitine, acetylcarnitine, lysoPC(16:0), proline, glutamic acid, pyroglutamic acid, leucine, pantothenic acid, tryptophan, indoleacrylic acid and citric acid, revealed a downward trend with the increase of dosage. Moreover, pathway analysis showed that these metabolites were associated with amino acid metabolism, energy metabolism and sphingolipid metabolism, which contributes to a further understanding of the toxicity mechanism of Corex Periplocae and its clinical safety. Additionally, we demonstrate that an UPLC-Q-TOF/MS-based metabolomic approach is a powerful tool and provides a promising approach for assessing the toxicity of traditional Chinese medicine and drug safety screening.

Topics: Amino Acids; Animals; Animals, Newborn; Biomarkers; Cardiotoxicity; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Energy Metabolism; Lipid Metabolism; Mass Spectrometry; Medicine, Chinese Traditional; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Saponins; Support Vector Machine