Research on Potential Toxic Mechanisms of Cardiotoxicity Induced by Podophyllotoxin to Male SD Rats Based on Toxicological Evidence Chain (TEC) Concept
Introduction: Podophyllotoxin (PPT) is a high-content and high-activity compound extracted from the traditional Chinese medicinal plant Dysosma versipellis (DV) which exhibits various biological activities. However, its severe toxicity limits its use. In clinical settings, patients with DV poisoning often experience adverse reactionswhen taking large doses in a short period. The heart is an important toxic targetorgan, so it is necessary to conduct 24-h acute cardiac toxicity studies on PPT tounderstand its underlying toxicity mechanism.Methods: Based on the concept of the toxicological evidence chain (TEC), weutilized targeted metabolomic and transcriptomic analyses to reveal themechanism of the acute cardiotoxicity of PPT. The manifestation of toxicity in Sprague-Dawley rats, including changes in weight and behavior, served as Injury Phenotype Evidence (IPE). To determine Adverse Outcomes Evidence (AOE), the hearts of the rats were evaluated through histopathological examination and by measuring myocardial enzyme and proinflammatory factor levels. Additionally, transcriptome analyses, metabolome analyses, myocardial enzymes, and cardiac injury markers were integrated to obtain Toxic Event Evidence (TEE) using correlation analysis.Results: The experiment showed significant epistaxis, hypokinesia, and hunched posture in PPT group rats within 24 hours after exposure to 120 mg/kg PPT. It is found that PPT induced cardiac injury in rats within 24 hours, as evidenced by increased serum myocardial enzyme levels, elevated concentrations of cardiac injury biomarkers, and altered cardiac cell morphology, all indicating some degree of cardiac toxicity. Transcriptome analysis revealed that primary altered metabolic pathway was arachidonic acid metabolism after PPT exposure. Cyp2e1, Aldob were positively correlated with differential metabolites, while DHA showed positive correlation with differential genes Fmo2 and Timd2, as well as with heart injury markers BNP and Mb.Conclusion:This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of PPT-induced acute cardiotoxicity, which involved oxidative stress, apoptosis, inflammatory response, and energy metabolism disorder.