Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds.
In breast cancer, in situ estrogen production has been demonstrated to play a major role in promoting tumor growth. Aromatase is the enzyme responsible for the conversion of androgen substrates into estrogens. This enzyme is highly expressed in breast cancer tissue compared with normal breast tissue. A wine extract fraction was recently isolated from red wine that exhibited a potent inhibitory action on aromatase activity. Using UV absorbance analysis, high-performance liquid chromatography profiling, accurate mass-mass spectrometry, and nanospray tandem mass spectrometry, most of the compounds in our red wine fraction were identified as procyanidin B dimers that were shown to be aromatase inhibitors. These chemicals have been found in high levels in grape seeds. Inhibition kinetic analysis on the most potent procyanidin B dimer has revealed that it competes with the binding of the androgen substrate with a K(i) value of 6 micro M. Because mutations at Asp-309, Ser-378, and His-480 of aromatase significantly affected the binding of the procyanidin B dimer, these active site residues are thought to be important residues that interact with this phytochemical. The in vivo efficacy of procyanidin B dimers was evaluated in an aromatase-transfected MCF-7 breast cancer xenograft model. The procyanidin B dimers were able to reduce androgen-dependent tumor growth, indicating that these chemicals suppress in situ estrogen formation. These in vitro and in vivo studies demonstrated that procyanidin B dimers in red wine and grape seeds could be used as chemopreventive agents against breast cancer by suppressing in situ estrogen biosynthesis.
Eng
Elizabeth T
ET
City of Hope Graduate School of Biological Science,Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA.
Ye
JingJing
J
Williams
Dudley
D
Phung
Sheryl
S
Moore
Roger E
RE
Young
Mary K
MK
Gruntmanis
Ugis
U
Braunstein
Glenn
G
Chen
Shiuan
S
D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology; D001141:Aromatase / Q000235:genetics; D047072:Aromatase Inhibitors; D044946:Biflavonoids; D002392:Catechin / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D007700:Kinetics; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed; D044945:Proanthocyanidins; D012639:Seeds; D027843:Vitis / Q000737:chemistry*; D014920:Wine
D016588:Anticarcinogenic Agents; D047072:Aromatase Inhibitors; D044946:Biflavonoids; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D044945:Proanthocyanidins; C479578:procyanidin B; C017674:procyanidin; D002392:Catechin; D001141:Aromatase