title: Dietary factors and the risk for acute infant leukemia: evaluating the effects of cocoa-derived flavanols on DNA topoisomerase activity.
abstract: There is cumulative strong evidence that diets rich in flavanols can provide certain positive health benefits, particularly with respect to the cardiovascular system. Consequently, it has been suggested that increasing one's dietary intake of flavanols may be of benefit. Complicating this idea, there are reports that high intakes of certain flavonoids during pregnancy are associated with an increased risk for acute infant leukemia due to a poison effect of select polyphenolic compounds on DNA topoisomerase (topo) II activity that promotes aberrant chromosomal translocations. In the current study, we characterized the effects of select flavanols (epicatechin and catechin monomers), and select flavanol dimers and longer oligomers, on topo II activity, and on cellular toxicity in vitro. In contrast to the chemotherapeutic drug etoposide (VP16) and the flavonol quercetin, which strongly inhibited topo II activity and increased the formation of cleavage complexes demonstrating a poison effect, the flavanols epicatechin and catechin had little effect on topo II enzyme activity. Accordingly, several fold greater concentrations of the flavanols were required to achieve cellular toxicity similar to that of quercetin and VP16 in cultures of myeloid and lymphoid cells. Low cellular toxicity and limited topo II inhibition were also observed with a procyanidin-rich cocoa extract. Of all the flavanols tested, the dimers (B2, B5 and a mix of both) exerted the greatest inhibition of topo II and inhibited cellular proliferation rates at concentrations similar to quercetin. However, in contrast to quercetin, the dimers did not function as topo II poisons. Collectively, our in vitro data show that cocoa-derived flavanols have limited effects on topo II activity and cellular proliferation in cancer cell lines. We predict that these compounds are likely to have limited leukemogenic potential at physiological concentrations.
authors.affiliation: Department of Nutrition, University of California, Davis, One Shields Ave, Davis, CA 95616, USA. llanoue@ucdavis.edu
authors.forename: Louise
authors.initials: L
authors.lastname: Lanoue
authors.forename: Kerri K
authors.initials: KK
authors.lastname: Green
authors.forename: Catherine
authors.initials: C
authors.lastname: Kwik-Uribe
authors.forename: Carl L
authors.initials: CL
authors.lastname: Keen
mesh_terms: D002099:Cacao / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D004032:Diet / Q000009:adverse effects*; D019281:Dimerization; D005047:Etoposide / Q000633:toxicity; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity*; D018922:HL-60 Cells; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000201:enzymology / Q000209:etiology; D011794:Quercetin / Q000633:toxicity; D012307:Risk Factors; D059005:Topoisomerase II Inhibitors
chemical_list: D005419:Flavonoids; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011794:Quercetin