Impact of the Pectenotoxin C-43 Oxidation Degree on Its Cytotoxic Effect on Rat Hepatocytes

The metabolism of toxins that have accumulated in fish and shellfish is considered a detoxification process, as happens with pectenotoxins (PTXs) in the Japanese scallop Patinopecten yessoensis. PTXs are macrolactones that display hepatotoxicity in mice, principally by capping or sequestering actin, their molecular target. PTX-2, which is considered to be the parental compound, oxidizes progressively to PTX-1, PTX-3, and PTX-6 in the Japanese scallop. In this study, we observed that PTX-1, PTX-6, and PTX-9 induce dose-dependent damage in the actin cytoskeleton and in the viability of primary cultured rat hepatocytes. In Clone 9 rat hepatocytes, PTX-1 and PTX-9 also affect the morphology of cells, but surprisingly, PTX-6 induced no effect. In accordance with this lack of activity, the actin cytoskeleton of CaCo-2 cells, another epithelial cell line, is not affected by PTX-6. In conclusion, the order of cytotoxicity of the analogues is PTX-2 > PTX-1 > PTX-6 > PTX-9. From a structure-activity perspective, the increase in the level of oxidation of the PTX molecule on C-43 decreases its cytotoxicity. Furthermore, PTX-6 is not able to induce effects on immortal cells while retaining its toxicity against primary cultured cells, whereas PTX-9, a 7-S-isomer, is active in both cellular models. The different cytotoxicities exerted by PTX-6 on cell lines and primary cells could be determined by the presence of a carboxylic acid group on C43 of the PTX molecule.