Effects of biochanin A on metabolism, DNA binding and mutagenicity of benzo[a]pyrene in mammalian cell cultures.
The search for potential chemopreventive agents from higher plants based upon alteration of benzo[a]pyrene (B[a]P) metabolism in cell cultures resulted in isolation of the isoflavone biochanin A. The mechanisms by which biochanin A inhibits the metabolic activation of B[a]P were investigated in hamster embryo cell cultures. Biochanin A treatment inhibited the metabolism of B[a]P to water-soluble metabolites. B[a]P-9,10-diol and B[a]P-7,8-diol by 44, 60 and 52% respectively. Biochanin A inhibited the formation of glucuronide conjugates from 3-OH-B[a]P and 9-OH-B[a]P. Biochanin A also inhibited, in a dose-dependent manner, oxidation of B[a]P by homogenate (S-9) of Aroclor 1254-induced rat liver. Exposure of hamster embryo cells to biochanin A and [3H]B[a]P resulted in a decrease in the total level of [3H]B[a]P bound to DNA compared with the control groups at all time points studied between 24 and 120 h. This decrease was due to reduction in the formation of DNA adducts from both (+)-anti-B[a]P-diolepoxide and (+)-syn-B[a]P-diolepoxide. In a hamster embryo cell-mediated V79 cell mutation assay, biochanin A treatment resulted in a dose-dependent reduction in the number of B[a]P-induced mutants. These results indicate that biochanin A inhibits metabolic activation of B[a]P to mutagenic intermediates and warrants further investigation as a potential chemopreventive agent.
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Y H
YH
Chae
S L
SL
Coffing
V M
VM
Cook
D K
DK
Ho
J M
JM
Cassady
W M
WM
Baird
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019833:Genistein; D005966:Glucuronidase / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D009369:Neoplasms / Q000517:prevention & control; D051381:Rats; D013997:Time Factors
D007529:Isoflavones; D009153:Mutagens; D001564:Benzo(a)pyrene; D004247:DNA; D019833:Genistein; D005966:Glucuronidase; C004541:biochanin A