Hepatoprotective activity of cucurbitacin

Cucurbit plant extracts have been used against various liver disorders in traditional medicine and their activity was thought to be due to the presence of cucurbitacin. Only a few liver protection studies were conducted on cucurbitacin in vivo. This is the first investigation to study cucurbitacin in vitro hepatoprotective activity on human hepatocyte-derived HepG2 and rat stellate cells-derived HSC-T6 cells.;A number of cucurbitacin analogues were isolated from Cucurbita texana and Citrullus lanatus. Semi-synthetic cucurbitacin were generated by alkylation, acetylation, and enzymatic hydrolysis. Cucurbitacin cytoprotection of HepG2 cells against CCl4-induced toxicity, and cucurbitacin anti-proliferative activity on HSC-T6 cells were studied. Cucurbitacin cytotoxicity was also measured to identify the non-toxic concentration for hepatoprotective activity screening. The IC50 of cucurbitacin on HepG2 cells ranged between 4 muM and 390 muM and between 2 muM and 256 muM on HSC-T6 cells. Natural analogs showed an 11-to-192 fold higher toxicity on HeLa cells than on HepG2 cells confirming the differential cytotoxicity of cucurbitacin.;Our study indicated that the majority of cucurbitacin had cytoprotective activity on HepG2 cells and the most active ten compounds EC50 ranged between 2.4 muM and 45.3 muM. A 3-to-9 folds less concentration than their IC50 was necessary to achieve 50% cytoprotection on HepG2 cells. Cucurbitacin demonstrated side effects on cell morphology at their EC50 concentration. In order to reduce toxicity and improve the margin between active and toxic dose, future studies should focus on other structural modifications.;All cucurbitacin analogs demonstrated high and novel anti-proliferation effect on serum-activated HSC-T6, and their EC50 ranged between 0.02 and 4.12 muM. An 8-to-344 folds less concentration than their IC 50 was necessary to achieve 50% anti-proliferation on HSC-T6 cells. No morphological changes were observed for the majority of the analogs. On both cell lines, the alkylated and alkyl-acetylated derivatives showed higher toxicity and lower or no activity. The rest of the cucurbitacin proved to have high potential as liver anti-fibrosis agents. (Abstract shortened by UMI.)...