Inhibitory effects of chrysoeriol on DNA adduct formation with benzo[a]pyrene in MCF-7 breast cancer cells.
Cytochrome P450 (CYP) 1 families including CYP1A1, 1A2 and 1B1 are well known to be deeply involved in the initiation of several cancers, due to the fact that they activate environmental pro-carcinogens to form ultimate carcinogens. Benzo[a]pyrene (BaP) is one of the major classes of prototypical pro-carcinogen. It is activated by the CYP1 family to its ultimate carcinogenic forms, mainly BaP-7,8-diol-9,10-epoxide (BPDE), and it forms adducts with DNA. This has been recognized to be a major initiation pathway for cancer. Our previous study demonstrated that chrysoeriol, which is a dietary methoxyflavonoid, selectively inhibited CYP1B1 enzymatic activity and might protect the CYP1B1 related-diseases such as breast cancer. In the present study, we further examined the effects of chrysoeriol on the other initiation pathway of cancer relating to the CYP1 family with BaP in human breast cancer MCF-7 cells. The effects of chrysoeriol on the formation of BPDE-DNA adducts were analyzed specifically using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. When MCF-7 cells were incubated with 2 microM BaP for 24h, three types of BPDE-dG adducts, especially (+)-trans-BPDE-dG as the dominant adduct, were detected. Co-treatment of MCF-7 cells with 10 microM chrysoeriol and BaP remarkably reduced (+)-trans-BPDE-dG formation. Chrysoeriol (1-10 microM) dose-dependently inhibited both EROD activity and the gene expressions of CYP1A1, 1B1 and 1A2 stimulated by treatment with BaP. In addition, the same amounts of chrysoeriol significantly inhibited the binding of BaP to the aryl hydrocarbon receptor (AhR), which is the key factor concerning the induction of the CYP1 families. In conclusion, our results clearly indicate that chrysoeriol inhibited the formation of BPDE-DNA adducts via regulation of the AhR pathway stimulated by BaP. As a consequence chrysoeriol may be involved in the chemoprevention of environmental pro-carcinogens such as BaP.
Takemura
Hitomi
H
Institute for Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga, Shizuoka 422-8526, Japan.
Nagayoshi
Haruna
H
Matsuda
Tomonari
T
Sakakibara
Hiroyuki
H
Morita
Maki
M
Matsui
Asako
A
Ohura
Takeshi
T
Shimoi
Kayoko
K
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000031:analogs & derivatives; D001189:Aryl Hydrocarbon Hydroxylases; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism* / Q000494:pharmacology*; D002274:Carcinogens, Environmental / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002477:Cells / Q000187:drug effects / Q000378:metabolism; D018890:Chemoprevention; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018736:DNA Adducts; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D005260:Female; D047309:Flavones; D005419:Flavonoids; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D002274:Carcinogens, Environmental; D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D047309:Flavones; D005419:Flavonoids; D018336:Receptors, Aryl Hydrocarbon; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C040060:7,8-dihydroxy-9,10-epoxide-7,8,9,10-tetrahydrobenzo(a)pyrene-10-deoxyguanosine; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D003849:Deoxyguanosine; C007054:chrysoeriol