Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II.
DNA topoisomerases (topos) and DNA polymerases (pols) are involved in many aspects of DNA metabolism such as replication reactions. We reported previously that long chain unsaturated fatty acids such as polyunsaturated fatty acids (PUFA) (i.e., eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA)) inhibited the activities of eukaryotic pols in vitro. In the present study, we found that PUFA also inhibited human topos I and II activities, and the inhibitory effect of conjugated fatty acids converted from EPA and DHA (cEPA and cDHA) on pols and topos was stronger than that of normal EPA and DHA. cEPA and cDHA inhibited the activities of mammalian pols and human topos, but did not affect the activities of plant and prokaryotic pols or other DNA metabolic enzymes tested. cEPA was a stronger inhibitor than cDHA with IC(50) values for mammalian pols and human topos of 11.0-31.8 and 0.5-2.5 microM, respectively. Therefore, the inhibitory effect of cEPA on topos was stronger than that on pols. Preincubation analysis suggested that cEPA directly bound both topos I and II, but did not bind or interact with substrate DNA. This is the first report that conjugated PUFA such as cEPA act as inhibitors of pols and topos. The results support the therapeutic potential of cEPA as a leading anti-cancer compound that poisons pols and topos.
Yonezawa
Yuko
Y
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Tsuzuki
Tsuyoshi
T
Eitsuka
Takahiro
T
Miyazawa
Teruo
T
Hada
Takahiko
T
Uryu
Keisuke
K
Murakami-Nakai
Chikako
C
Ikawa
Hiroshi
H
Kuriyama
Isoko
I
Takemura
Masaharu
M
Oshige
Masahiko
M
Yoshida
Hiromi
H
Sakaguchi
Kengo
K
Mizushina
Yoshiyuki
Y
D000818:Animals; D002384:Catalysis; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D015118:Eicosapentaenoic Acid / Q000737:chemistry*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D013696:Temperature; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D015118:Eicosapentaenoic Acid; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II