title: Isoform selective inhibition and inactivation of human cytochrome P450s by methylenedioxyphenyl compounds.
abstract: 1. A series of methylenedioxyphenyl compounds were evaluated for their inhibitory and inactivation effects on nine human cytochrome P450 (CYP) activities using microsomes from human B-lymphoblast cells expressing specific human CYP isoforms. 2. Methylenedioxyphenyl compounds which possess a bulky structure such as 1,4-benzothiazine showed substantial inhibition of S-warfarin 7-hydroxylation catalysed by CYP2C9, S-mephenytoin 4'-hydroxylation by CYP2C19, bufuralol 1'-hydroxylation by CYP2D6, and testosterone 6beta-hydroxylation by CYP3A4. Regarding ethoxyresorufin O-deethylation catalysed by CYP1A1 and benzyloxyresorufin O-dealkylation by CYP2B6, the subtle change of a substitution of the 1,4-benzothiazine structure affected the inhibition selectivity. Ethoxyresorufin O-deethylation by CYP1A2, coumarin 7-hydroxylation by CYP2A6, and chlorzoxazone 6-hydroxylation by CYP2E1 were not inhibited by almost any of the methylenedioxyphenyl compounds. The inhibitory effects of methylenedioxyphenyl compounds that possess a short chain amino group on the human CYP isoforms were not significant. 3. The methylenedioxyphenyl compounds inactivated CYP1A1 (k(inact) = 0.034 min(-1) and K(i) = 0.81 microM), CYP2C9 (k(inact) = 0.041 and 0.042 min(-1) and K(i) = 0.56 and 0.15 microM), CYP2D6 (k(inact) = 0.044-0.339 min(-1) and K(i) = 0.21-19.88 microM), and CYP3A4 (k(inact) = 0.076-0.251 min(-1) and K(i) = 0.25-0.69 microM). These results suggested that the methylenedioxyphenyl compounds investigated in this study would be potent mechanism-based inactivators of these human CYP isoforms. In contrast, CYP2B6 and CYP2C19 were not inactivated. 4. The present study suggested that the selectivity of inhibition or inactivation of human CYP isoforms by methylenedioxyphenyl compounds may vary according to the structure of the side chain.
authors.affiliation: Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: R
authors.initials: R
authors.lastname: Yamaji
authors.forename: H
authors.initials: H
authors.lastname: Takashina
authors.forename: N
authors.initials: N
authors.lastname: Shimada
authors.forename: H
authors.initials: H
authors.lastname: Yamazaki
authors.forename: T
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013844:Thiazoles; D003577:Cytochrome P-450 Enzyme System; C064356:sesamodil; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C045793:CYP2C19 protein, human; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; D019362:Cytochrome P-450 CYP2B1; D065731:Cytochrome P-450 CYP2C19; C022724:testosterone 7-alpha-hydroxylase, hamster