Identification of metabolic pattern and bioactive form of resveratrol in human medulloblastoma cells.
Cancer preventive reagent trans-resveratrol is intracellularly biotransformed to different metabolites. However, it is still unclear whether trans-resveratrol exerts its biological effects directly or through its metabolite(s). This issue was addressed here by identifying the metabolic pattern and the bioactive form of resveratrol in a resveratrol-sensitive human medulloblastoma cell line, UW228-3. The cell lysates and condition media of UW228-3 cells with or without 100 microM resveratrol treatment were analyzed by HPLC and LC/MS which revealed (1) that resveratrol was chemically unstable and the spontaneous generation of cis-resveratrol reduced resveratrol's anti-medulloblastoma efficacy and (2) that resveratrol monosulfate was the major metabolite of the cells. To identify the bioactive form of resveratrol, a mixture-containing approximately half fraction of resveratrol monosulfate was prepared by incubating trans-resveratrol with freshly prepared rat brain lysates. Medulloblastoma cells treated by 100 microM of this mixture showed attenuated cell crisis. The overall levels of the three brain-associated sulfotransferases (SULT1A1, 1C2 and 4A1) were low in medulloblastoma cells in vivo and in vitro in comparison with that in human noncancerous and rat normal cerebella; resveratrol could more or less up-regulate the production of these enzymes in UW228-3 cells but their overall level was still lower than that in normal cerebellum tissue. Our study thus demonstrated for the first time that trans-resveratrol is the bioactive form in medulloblastoma cells in which the expression of brain-associated SULTs was down-regulated, resulting in the increased intracellular bioavailability and anti-medulloblastoma efficacy of trans-resveratrol.
Shu
Xiao-Hong
XH
Department of Cell Biology, Dalian Medical University, China.
Li
Hong
H
Sun
Zheng
Z
Wu
Mo-Li
ML
Ma
Jing-Xin
JX
Wang
Jian-Min
JM
Wang
Qian
Q
Sun
Yuan
Y
Fu
Yuan-Shan
YS
Chen
Xiao-Yan
XY
Kong
Qing-You
QY
Liu
Jia
J
D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy*; D051381:Rats; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D015238:Sulfotransferases / Q000378:metabolism; D055815:Young Adult
D000970:Antineoplastic Agents; D013267:Stilbenes; D015238:Sulfotransferases; D000077185:Resveratrol