In vitro evaluation of the cytotoxicity of several eremophilane constituents of Petasites hybridus in rat hepatocytes

Several Petasites hybridus eremophilanes have been tested for cytotoxicity in primary rat hepatocytes by means of the MTT assay [1, 2, 3]. (8S)-8-Hydroxyeremophil-7(11)-en-12,8-olide, (8R,9β)-2-[(Angeloyl)oxy]-9-hydroxyeremophil-7(11)-en-12,8-olide and (8S)-2-[Methacroyl)oxy]eremophil-7(11)-en-12,8-olide were not cytotoxic up to a concentration of 0.5mg/mL. No EC₅₀ values were determinable for these less soluble compounds. (8S)-2-{[(Z)-3-(Methylsulfanyl)prop-2-enoyl]oxy}eremophil-7(11)-en-12,8-olide was not cytotoxic up to 1mg/mL. (8R)-2-[Methacroyl)oxy]eremophil-7(11)-en-12,8-olide was the most cytotoxic constituent (EC₅₀ approx. 0.3mg/mL). The non-steroid-like 8α-conformers of both 8-H-isomeric couples of the 2-angeloyloxy and 2-methacroyloxy esters of eremophilanolide seemed to be more cytotoxic than the steroid-like 8β-H-conformers. The additionally measured cytotoxicity parameters mitochondrial dehydrogenase activity, ATP-content and LDH-leakage were considerably lower for the 8α-conformer of 2-[Methacroyl)oxy]eremophil-7(11)-en-12,8-olide than for the corresponding 8β-conformer [4]. This stereoselectivity points to a specific new cytotoxicity target.

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