title: Effect of Ginkgo biloba extract on procarcinogen-bioactivating human CYP1 enzymes: identification of isorhamnetin, kaempferol, and quercetin as potent inhibitors of CYP1B1.
abstract: In the present study, we investigated the effect of Ginkgo biloba extracts and some of its individual constituents on the catalytic activity of human cytochrome P450 enzymes CYP1B1, CYP1A1, and CYP1A2. G. biloba extract of known abundance of terpene trilactones and flavonol glycosides inhibited 7-ethoxyresorufin O-dealkylation catalyzed by human recombinant CYP1B1, CYP1A1, and CYP1A2, and human liver microsomes, with apparent Ki values of 2 +/- 0.3, 5 +/- 0.5, 16 +/- 1.4, and 39 +/- 1.2 microg/ml (mean +/- SE), respectively. In each case, the mode of inhibition was of the mixed type. Bilobalide, ginkgolides A, B, C, and J, quercetin 3-O-rutinoside, kaempferol 3-O-rutinoside, and isorhamentin 3-O-rutinoside were not responsible for the inhibition of CYP1 enzymes by G. biloba extract, as determined by experiments with these individual chemicals at the levels present in the extract. In contrast, the aglycones of quercetin, kaempferol, and isorhamentin inhibited CYP1B1, CYP1A1, and CYP1A2. Among the three flavonol aglycones, isorhamentin was the most potent in inhibiting CYP1B1 (apparent Ki = 3 +/- 0.1 nM), whereas quercetin was the least potent in inhibiting CYP1A2 (apparent Ki = 418 +/- 50 nM). The mode of inhibition was competitive, noncompetitive, or mixed, depending on the enzyme and the flavonol. G. biloba extract also reduced benzo[a]pyrene hydroxylation, and the effect was greater with CYP1B1 than with CYP1A1 as the catalyst. Overall, our novel findings indicate that G. biloba extract and the flavonol aglycones isorhamnetin, kaempferol, and quercetin preferentially inhibit the in vitro catalytic activity of human CYP1B1.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. tchang@interchange.ubc.ca
authors.forename: Thomas K H
authors.initials: TK
authors.lastname: Chang
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Eugene Y H
authors.initials: EY
authors.lastname: Yeung
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001564:Benzo(a)pyrene / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D002384:Catalysis; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065633:Cytochrome P-450 CYP1B1; D003640:Dealkylation; D004305:Dose-Response Relationship, Drug; D044948:Flavonols / Q000494:pharmacology; D020441:Ginkgo biloba; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D044949:Kaempferols / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology / Q000031:analogs & derivatives; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
chemical_list: D002273:Carcinogens; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D044948:Flavonols; D044949:Kaempferols; D010936:Plant Extracts; D011994:Recombinant Proteins; C047368:3-methylquercetin; D001564:Benzo(a)pyrene; C006552:kaempferol; D011794:Quercetin; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1