Warifteine and milonine, alkaloids isolated from Cissampelos sympodialis Eichl: cytotoxicity on rat hepatocyte culture and in V79 cells.
Two alkaloids were isolated from the leaves of Cissampelos sympodialis; a bisbenzylisoquinoline compound named warifteine and a novel 8,14-dihydromorphinandienone alkaloid named milonine. The cytotoxic effects of these alkaloids were assayed in cultured hepatocytes and V79 fibroblasts. Three independent endpoint assays for cytotoxicity in vitro were used: the nucleic acid content (NAC), tetrazolium reduction (MTT) and neutral red uptake (NRU). Milonine was less toxic than warifteine in both cell cultures. The IC50 values determined in the three different viability assays were around 100 and 400 microM after milonine treatment of V79 cells or hepatocytes. IC50 values ranging from 10 to 35 microM were obtained for warifteine in the viability tests evaluated in V79 cells and hepatocytes. Due to the similar cytotoxic effects detected on V79 cells and hepatocytes, probably warifteine and milonine induced toxic effects independent to the cytochrome P450. This hypothesis was corroborated by the results where Cimetidine (1.0 mM), a traditional cytochrome P450 inhibitor, did not protect the cells from the toxic action of warifteine or milonine. In conclusion, these alkaloids merit further investigations as potential novel pharmacological agents although milonine was less toxic than warifteine in the cells models investigated.
Melo
Patricia Silva
PS
Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), CP 6110, Campinas, SP 13083-970, Brazil. pmelo@unicamp.br
de Medeiros Cavalcante
Horacinna Maria
HM
Barbosa-Filho
José Maria
JM
de Fátima Formiga Melo Diniz
Margareth
M
de Medeiros
Isac Almeida
IA
Haun
Marcela
M
D000470:Alkaloids / Q000302:isolation & purification / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002927:Cimetidine / Q000494:pharmacology; D031606:Cissampelos / Q000737:chemistry*; D004396:Coloring Agents / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D005562:Formazans; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009499:Neutral Red / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013778:Tetrazolium Salts
D000470:Alkaloids; D004396:Coloring Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005562:Formazans; D013778:Tetrazolium Salts; C079782:MTT formazan; D009499:Neutral Red; C003931:warifteine; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System