Effects of synthetic and naturally occurring flavonoids on metabolic activation of benzo[a]pyrene in hamster embryo cell cultures.
Biochanin A, an isoflavone, has previously been shown to inhibit the metabolic activation of the carcinogen benzo[a]pyrene (B[a]P) to metabolites that bind to DNA in hamster embryo cells and are mutagenic in Chinese hamster V79 cells. To determine the structural features required for this activity and to attempt to find more effective inhibitors, a series of synthetic and naturally occurring flavonids were tested for their ability to modulate B[a]P metabolism in hamster embryo cell cultures. The observed structure-activity relationships indicate that the structural features of flavonoids important for effective inhibition of B[a]P metabolism in hamster embryo cells are the presence of two hydroxyl, two methoxyl, or methyl and hydroxyl substituents at the 5- and 7-positions and a 2,3-double bond. Flavones are slightly better inhibitors of B[a]P metabolism than the corresponding isoflavones. A substituent at the 4'-position is not essential for inhibition of B bdP metabolism. The presence of a hydroxyl group at position 3 slightly enhances activity. Apigenin, acacetin and kaempferide are effective inhibitors of B[a]P-induced mutagenesis in a hamster embryo cell-mediated V79 cell mutation assay. However, apigenin is cytotoxic at the inhibitory dose, whereas acacetin and kaempferide are not. These results suggest that acacetin and kaempferide are promising candidates for in vivo testing as potential chemopreventive agents.
Chae
Y H
YH
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Purdue University, West Lafayette, IN 47907.
Ho
D K
DK
Cassady
J M
JM
Cook
V M
VM
Marcus
C B
CB
Baird
W M
WM
D000818:Animals; D001564:Benzo(a)pyrene / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001711:Biotransformation; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D004622:Embryo, Mammalian; D005419:Flavonoids / Q000494:pharmacology*; D008647:Mesocricetus; D009152:Mutagenicity Tests / Q000379:methods; D013329:Structure-Activity Relationship
D005419:Flavonoids; D001564:Benzo(a)pyrene