Structural basis for DNA-cleaving activity of resveratrol in the presence of Cu(II).
Resveratrol (1, 3,5,4'-trihydroxy-trans-stilbene), a polyphenol found in grapes and other food products, is known as an antioxidant and cancer chemopreventive agent. However, 1 was shown to induce genotoxicity through a high frequency of micronucleus and sister chromatid exchange in vitro and DNA-cleaving activity in the presence of Cu(II). The present study was designed to explore the structure-activity relationship of 1 in DNA strand scission and to characterize the substrate specificity for Cu(II) and DNA binding. When pBR322DNA was incubated with 1 or its analogues differing in the number and positions of hydroxyl groups in the presence of Cu(II), the ability of 4-hydroxystilbene analogues to induce DNA strand scission is much stronger than that of 3-hydroxy analogues. The high binding affinity with both Cu(II) and DNA was also observed by 4-hydroxystilbene analogues. The reduction of Cu(II) which is essential for activation of molecular oxygen proceeded by addition of 1 to the solution of the Cu(II)-DNA complex, while such reduction was not observed with the addition of isoresveratrol, in which the 4-hydroxy group of 1 is changed to the 3-position. The results show that the 4-hydroxystilbene structure of 1 is a major determinant of generation of reactive oxygen species that was responsible for DNA strand scission.
Fukuhara
Kiyoshi
K
Division of Organic Chemistry, National Institute of Health Sciences, Tokyo, Japan. fukuhara@nihs.go.jp
Nagakawa
Maki
M
Nakanishi
Ikuo
I
Ohkubo
Kei
K
Imai
Kohei
K
Urano
Shiro
S
Fukuzumi
Shunichi
S
Ozawa
Toshihiko
T
Ikota
Nobuo
N
Mochizuki
Masataka
M
Miyata
Naoki
N
Okuda
Haruhiro
H
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001665:Binding Sites; D002413:Cations, Divalent; D003300:Copper / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D017665:Hydroxyl Radical / Q000378:metabolism; D017382:Reactive Oxygen Species; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D002413:Cations, Divalent; D017382:Reactive Oxygen Species; D013267:Stilbenes; D017665:Hydroxyl Radical; C064297:4-hydroxystilbene; D003300:Copper; D004247:DNA; D000077185:Resveratrol