Modulation of CYP1B1 and CYP1A1 gene expression and activation of aryl hydrocarbon receptor by Ginkgo biloba extract in MCF-10A human mammary epithelial cells.
The aryl hydrocarbon receptor (AhR) signaling pathway regulates the production of CYP1B1 and CYP1A1, which catalyze the bioactivation of various procarcinogens. In the present study, we investigated the effect of Ginkgo biloba extract and some of its chemical constituents on CYP1B1 and CYP1A1 gene expression and AhR activity in cultured MCF-10A human mammary epithelial cells. Treatment of MCF-10A cells with noncytotoxic concentrations of G. biloba extract (25-300 microg/mL for 24 or 48 h) increased CYP1B1 and CYP1A1 mRNA expression, which was accompanied by an increase in CYP1-mediated ethoxyresorufin O-dealkylation activity. The inductive effects of G. biloba extract were attenuated by an AhR antagonist (3',4'-dimethoxyflavone). G. biloba extract (25-300 microg/mL) increased AhR-dependent reporter activity, as determined in MCF-10A cells transfected with an AhR-regulated luciferase reporter plasmid (pGudluc6.1). Bilobalide and ginkgolides A, B, C, and J were not responsible for the modulation of CYP1B1 and CYP1A1 gene expression or AhR activation by G. biloba extract. In contrast, quercetin increased CYP1B1 and CYP1A1 gene expression and activated AhR, whereas kaempferol and isorhamnetin suppressed constitutive CYP1B1 expression and antagonized AhR activation by benzo[a]pyrene. Overall, our findings provide an impetus for future investigations on the effect of G. biloba extract in CYP1-mediated chemical carcinogenesis.
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Ganesh
G
Rajaraman
Guixiang
G
Yang
Jie
J
Chen
Thomas K H
TK
Chang
D001189:Aryl Hydrocarbon Hydroxylases; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter; D020441:Ginkgo biloba / Q000737:chemistry*; D006801:Humans; D049409:Luciferases, Firefly / Q000235:genetics; D049410:Luciferases, Renilla / Q000235:genetics; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D010957:Plasmids; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D018076:DNA, Complementary; D010936:Plant Extracts; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1