CYP1-mediated metabolism of dietary flavonoids enhances their toxicity in breast cancer cells.
Among the different mechanisms proposed to explain the toxic effects of dietary flavonoids towards cancerous cells, substratelike interactions with cytochrome P450 CYP1 enzymes have recently been explored. In the present study the metabolism of the flavonoids chrysin, baicalein, scutellarein, sinensetin and genkwanin by recombinant CYP1A1, CYP1B1 and CYP1A2 enzymes and their cytotoxicity in MDA-MB 468 human breast adenocarcinoma and MCF-10A normal breast cell lines, were investigated. Baicalein and 6-hydroxyluteolinwere the only conversion products of chrysin and scutellarein metabolism by CYP1 family enzymes respectively, while baicalein itself was not further metabolized. Sinensetin and genkwanin produced a greater number of metabolites and were shown to inhibit strongly in vitro proliferation of MDA-MB 468 cells at submicromolar and micromolar concentrations respectively, without essentially affecting the viability of MCF-10A cells. Cotreatment of the CYP1 family inhibitor acacetin reversed the toxicity noticed for these two flavones in MDA-MB 468 cells to 10_M. In contrast chrysin, baicalein and scutellarein inhibited proliferation of MDA-MB 468 cells to a lesser extent than sinensetin and genkwanin. The metabolism of genkwanin to apigenin and of chrysin to baicalein was favored by CYP1B1 and CYP1A1 respectively. Taken together the data suggests that CYP1 family enzymes contribute amajor part to the activation of dietary flavonoids to more toxic conversion products in breast cancer cells.
Citation : Androutsopoulos, V., Ruparelia, K., Arroo, R., Tsatsakis, A. and Spandidos, D. (2009) CYP1-mediated metabolism of dietary flavonoids enhances their toxicity in breast cancer cells. Toxicology Letters, 189S, S113.
ISSN : 0378-4274
Research Group : Chemistry for Health
Research Institute : Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)
Peer Reviewed : Yes
- Leicester School of Pharmacy