Structure-related cytotoxicity and anti-hepatofibric effect of asiatic acid derivatives in rat hepatic stellate cell-line, HSC-T6.
The structural relationship of 16 asiatic acid (AA) derivatives, including AA and asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6 cells, were investigated. Cytotoxicities of AA derivatives varied from 5.5 microM to over 2000 microM of IC50 depending on AA functional group modifications. Substituting the hydroxyl group at the C(2) to N[triple bond]C and substituting bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly reduced it. Modification of the carboxylic acid group at C28 also reduced the cytotoxicity. The collagen synthesis determined by hydroxyproline content in the cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA derivatives. The anti-hepatofibrotic effect of these compounds might be due to the reduced expression of prolyl 4-hydroxylase alpha and beta subunits and TIMP2. However, the inhibition of collagen by asiaticoside derivatives did not show any structural-activity relationship.
Dong
Mi-Sook
MS
School of Life sciences and Biotechnology, Korea University, Seoul 136-701, Korea. msdong@korea.ac.kr
Jung
Seung-Hyun
SH
Kim
Hyun-jung
HJ
Kim
Jeong-Ran
JR
Zhao
Long-Xuan
LX
Lee
Eung-Seok
ES
Lee
Eun-Joo
EJ
Yi
Jung Bum
JB
Lee
Namkyu
N
Cho
Yong-Baik
YB
Kwak
Wie Jong
WJ
Park
Young In
YI
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D053978:Pentacyclic Triterpenes; D051381:Rats; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry* / Q000633:toxicity*
D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C017032:asiatic acid