title: Effects of green tea catechins on cytochrome P450 2B6, 2C8, 2C19, 2D6 and 3A activities in human liver and intestinal microsomes.
abstract: The effects of green tea catechins on the main drug-metabolizing enzymatic system, cytochrome P450 (CYP), have not been fully elucidated. The objective of the present study was to evaluate the effects of green tea extract (GTE, total catechins 86.5%, w/w) and (-)-epigallocatechin-3-gallate (EGCG) on the activities of CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A in vitro, using pooled human liver and intestinal microsomes. Bupropion hydroxylation, amodiaquine N-deethylation, (S)-mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation and midazolam 1'-hydroxylation were assessed in the presence or absence of various concentrations of GTE and EGCG to test their effects on CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A activities, respectively. Each metabolite was quantified using UPLC/ESI-MS, and the inhibition kinetics of GTE and EGCG on CYP enzymes was analyzed. In human liver microsomes, IC50 values of GTE were 5.9, 4.5, 48.7, 25.1 and 13.8 µg/mL, for CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A, respectively. ECGC also inhibited these CYP isoforms with properties similar to those of GTE, and produced competitive inhibitions against CYP2B6 and CYP2C8, and noncompetitive inhibition against CYP3A. In human intestinal microsomes, IC50 values of GTE and EGCG for CYP3A were 18.4 µg/mL and 31.1 µM, respectively. EGCG moderately inhibited CYP3A activity in a noncompetitive manner. These results suggest that green tea catechins cause clinically relevant interactions with substrates for CYP2B6 and CYP2C8 in addition to CYP3A.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Japan. misaka@fmu.ac.jp
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawabe
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: José Pablo
authors.initials: JP
authors.lastname: Werba
authors.forename: Monica
authors.initials: M
authors.lastname: Giroli
authors.forename: Sekihiro
authors.initials: S
authors.lastname: Tamaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kan
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006801:Humans; D020128:Inhibitory Concentration 50; D007422:Intestines / Q000166:cytology; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D010936:Plant Extracts; C400322:cytochrome P-450 CYP2C subfamily; D002392:Catechin; D003577:Cytochrome P-450 Enzyme System; C045651:epigallocatechin gallate; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C045793:CYP2C19 protein, human; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19