Gastroprotective and ulcer-healing activity of oleanolic acid derivatives: in vitro-in vivo relationships.
The triterpene oleanolic acid 1 and its semisynthetic derivatives 2-7 were assessed for gastroprotective and ulcer-healing effect using human epithelial gastric cells (AGS) and human lung fibroblasts (MRC-5). The ability of the compounds to protect the AGS cells against the damage induced by sodium taurocholate (NaT), to stimulate the cellular reduced glutathione (GSH) and prostaglandin E(2) content, to enhance AGS and MRC-5 cell proliferation and to scavenge superoxide anion in vitro was studied. The cytotoxicity of the compounds was assessed towards MRC-5 and AGS cells. In addition, the gastroprotective activity of the compounds was assessed in vivo using the HCl/EtOH-induced ulcer model in mice. All the assayed compounds displayed a significant reduction of AGS cells damage after incubation with NaT. None of the studied compounds was active as a superoxide anion scavenger nor stimulated the GSH content in AGS cell cultures. Compounds 1, 2, 4 and 6 were able to increase the prostaglandin content in AGS cell cultures. Concerning the proliferation assays, a significant stimulating effect was observed for compounds 3 and 7 on AGS cells and for 1 and 7 on MRC-5 fibroblasts. Regarding cytotoxicity, derivatives 2, 4, 6 and 7 were less toxic than the parent compound oleanolic acid. Our results strongly support the predictive capacity of the in vitro assessment of gastroprotective activity allowing the reduction of experimental animals.
Sánchez
Marianela
M
Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla 747, Talca, Chile.
Theoduloz
Cristina
C
Schmeda-Hirschmann
Guillermo
G
Razmilic
Iván
I
Yáñez
Tania
T
Rodríguez
Jaime A
JA
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002492:Central Nervous System Depressants; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells; D000431:Ethanol; D005347:Fibroblasts; D016166:Free Radical Scavengers / Q000494:pharmacology; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006851:Hydrochloric Acid; D064747:Lansoprazole; D008297:Male; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D009853:Omeprazole / Q000031:analogs & derivatives / Q000494:pharmacology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism; D013656:Taurocholic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000897:Anti-Ulcer Agents; D002492:Central Nervous System Depressants; D016166:Free Radical Scavengers; D064747:Lansoprazole; D013481:Superoxides; D000431:Ethanol; D013656:Taurocholic Acid; D009828:Oleanolic Acid; D005978:Glutathione; D015232:Dinoprostone; D009853:Omeprazole; D006851:Hydrochloric Acid