title: In vitro inhibition of human CYP2E1 and CYP3A by quercetin and myricetin in hepatic microsomes is not gender dependent.
abstract: This is the first in vitro study to investigate gender-related differences in the regulation of human cytochrome P450 by the flavonoids. Activities of CYP2E1 and CYP3A were measured in the presence of quercetin, myricetin, or isorhamnetin in hepatic microsomal pools from male and female donors. Hydroxylation of p-nitrophenol (PNPH) was measured to determine CYP2E1 activity, and O-dealkylation of 7-benzyloxy-4-trifluoromethylcoumarin (BFC) was measured to determine CYP3A activity. Quercetin, but not myricetin or isorhamnetin, competitively inhibited PNPH activity in human recombinant cDNA-expressed CYP2E1 with the Ki=52.1±6.31μM. In the human microsomes, slight inhibition of PNPH activity by quercetin was not considered as physiologically relevant. Quercetin inhibited BFC activity in human recombinant cDNA-expressed CYP3A4 competitively with the Ki=15.4±1.52μM, and myricetin - noncompetitively with the Ki=74.6±7.99μM. The degree of inhibition by quercetin was similar between genders. Myricetin showed somewhat stronger inhibition in female pools, but the Ki values were higher than physiologically relevant concentrations. Isorhamnetin did not affect either PNPH or BFC activity. We concluded that observed inhibition of CYP2E1 and CYP3A by some flavonols were not gender-dependent.
authors.affiliation: Swedish University of Agricultural Sciences, Department of Molecular Sciences, Box 7015, 750 07, Uppsala, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Östlund
authors.affiliation: University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Zatisi 728/II, 389 25, Vodnany, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Zlabek
authors.affiliation: Swedish University of Agricultural Sciences, Department of Molecular Sciences, Box 7015, 750 07, Uppsala, Sweden; University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Zatisi 728/II, 389 25, Vodnany, Czech Republic. Electronic address: Galia.Zamaratskaia@slu.se.
authors.forename: Galia
authors.initials: G
authors.lastname: Zamaratskaia
mesh_terms: D003374:Coumarins / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012737:Sex Factors
chemical_list: C419147:7-benzyloxy-4-trifluoromethylcoumarin; D003374:Coumarins; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009596:Nitrophenols; C047368:3-methylquercetin; C040015:myricetin; D011794:Quercetin; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; C024836:4-nitrophenol
keywords: Cytochrome P450; Females; Flavonols; Hepatic microsomes; Males; isorhamnetin (PubChem CID: 5281654); myricetin (PubChem CID: 5281672); quercetin (PubChem CID: 5280343)