Acetogenins are cell-membrane permeable, naturally occurring secondary metabolites of plants such as Annonaceae, Lauraceae and other related phylogenic families. They belong to the chemical derivatives of polyketides, which are synthesized from fatty acid pre-cursors. Although acetogenins have displayed diverse biological activities, the anti-proliferative effect on human cancer cells has been widely reported. Acetogenins are inhib-itors of complex I in the electron transport chain therefore they interrupt ATP synthesis in mitochondria. We tested a new acetogenins-enriched extract from the seed of Persea ameri-cana in order to investigate if any toxicity was induced on cardiac tissue and determine the involved mechanism. In isolated perfused heart we found that contractility was com-pletely inhibited at an accumulative dose of 77 μg/ml. In isolated cardiomyocytes, the acetogenins-enriched extract induced apoptosis through the activation of the intrinsic path-way at 43 μg/ml. In isolated mitochondria, it inhibited com-plex I activity on NADH-linked respiration, as would be expected, but also induced permeability transition on succinate-linked respiration. Cyclosporine A, a known blocker of permeability transition, significantly prevented the perme-ability transition triggered by the acetogenins-enriched extract. In addition, our acetogenins-enriched extract inhibited ADP/ ATP exchange, suggesting that an important element in phos-phate or adenylate transport was affected. In this manner we suggest that acetogenins-enriched extract from Persea ameri-cana could directly modulate permeability transition, an entity not yet associated with the acetogenins' direct effects, resulting in cardiotoxicity.