PMID- 18461976
OWN - NLM
STAT- MEDLINE
DCOM- 20081209
LR  - 20211020
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Print)
IS  - 0893-228X (Linking)
VI  - 21
IP  - 6
DP  - 2008 Jun
TI  - Dietary polyphenols as topoisomerase II poisons: B ring and C ring substituents 
      determine the mechanism of enzyme-mediated DNA cleavage enhancement.
PG  - 1253-60
LID - 10.1021/tx8000785 [doi]
AB  - Dietary polyphenols are a diverse and complex group of compounds that are linked 
      to human health. Many of their effects have been attributed to the ability to 
      poison (i.e., enhance DNA cleavage by) topoisomerase II. Polyphenols act against 
      the enzyme by at least two different mechanisms. Some compounds are traditional, 
      redox-independent topoisomerase II poisons, interacting with the enzyme in a 
      noncovalent manner. Conversely, others enhance DNA cleavage in a redox-dependent 
      manner that requires covalent adduction to topoisomerase II. Unfortunately, the 
      structural elements that dictate the mechanism by which polyphenols poison 
      topoisomerase II have not been identified. To resolve this issue, the activities 
      of two classes of polyphenols against human topoisomerase IIalpha were examined. 
      The first class was a catechin series, including (-)-epigallocatechin gallate 
      (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and 
      (-)-epicatechin (EC). The second was a flavonol series, including myricetin, 
      quercetin, and kaempferol. Compounds were categorized into four distinct groups: 
      EGCG and EGC were redox-dependent topoisomerase II poisons, kaempferol and 
      quercetin were traditional poisons, myricetin utilized both mechanisms, and ECG 
      and EC displayed no significant activity. On the basis of these findings, a set 
      of rules is proposed that predicts the mechanism of bioflavonoid action against 
      topoisomerase II. The first rule centers on the B ring. While the C4'-OH is 
      critical for the compound to act as a traditional poison, the addition of -OH 
      groups at C3' and C5' increases the redox activity of the B ring and allows the 
      compound to act as a redox-dependent poison. The second rule centers on the C 
      ring. The structure of the C ring in the flavonols is aromatic and planar and 
      includes a C4-keto group that allows the formation of a proposed pseudo ring with 
      the C5-OH. Disruption of these elements abrogates enzyme binding and precludes 
      the ability to function as a traditional topoisomerase II poison.
FAU - Bandele, Omari J
AU  - Bandele OJ
AD  - Department of Biochemistry, Vanderbilt UniVersity School of Medicine, Nashville, 
      Tennessee 37232-0146, USA.
FAU - Clawson, Sara J
AU  - Clawson SJ
FAU - Osheroff, Neil
AU  - Osheroff N
LA  - eng
GR  - R01 GM033944-24/GM/NIGMS NIH HHS/United States
GR  - T32 CA009582/CA/NCI NIH HHS/United States
GR  - GM33944/GM/NIGMS NIH HHS/United States
GR  - R01 GM033944-25/GM/NIGMS NIH HHS/United States
GR  - 5 T32 CA09582/CA/NCI NIH HHS/United States
GR  - R01 GM033944/GM/NIGMS NIH HHS/United States
GR  - F31 GM78744/GM/NIGMS NIH HHS/United States
GR  - F31 GM078744/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080508
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Flavonoids)
RN  - 0 (Phenols)
RN  - 0 (Polyphenols)
RN  - 0 (Tea)
RN  - 0 (Topoisomerase II Inhibitors)
RN  - 8R1V1STN48 (Catechin)
RN  - EC 5.99.1.3 (DNA Topoisomerases, Type II)
SB  - IM
MH  - Catechin/pharmacology
MH  - Color
MH  - DNA Cleavage/*drug effects
MH  - DNA Topoisomerases, Type II/metabolism
MH  - *Diet
MH  - Flavonoids/administration & dosage/*chemistry/*pharmacology
MH  - Humans
MH  - Phenols/administration & dosage/*chemistry/*pharmacology
MH  - Polyphenols
MH  - Tea/chemistry
MH  - *Topoisomerase II Inhibitors
PMC - PMC2737509
MID - NIHMS126192
EDAT- 2008/05/09 09:00
MHDA- 2008/12/17 09:00
PMCR- 2009/09/03
CRDT- 2008/05/09 09:00
PHST- 2008/05/09 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/05/09 09:00 [entrez]
PHST- 2009/09/03 00:00 [pmc-release]
AID - 10.1021/tx8000785 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2008 Jun;21(6):1253-60. doi: 10.1021/tx8000785. Epub 2008 May 
      8.