title: Identification of cytochrome P450 2D6 and 2C9 substrates and inhibitors by QSAR analysis.
abstract: This paper presents four new QSAR models for CYP2C9 and CYP2D6 substrate recognition and inhibitor identification based on human clinical data. The models were used to screen a large data set of environmental chemicals for CYP activity, and to analyze the frequency of CYP activity among these compounds. A large fraction of these chemicals were found to be CYP active, and thus potentially capable of affecting human physiology. 20% of the compounds within applicability domain of the models were predicted to be CYP2C9 substrates, and 17% to be inhibitors. The corresponding numbers for CYP2D6 were 9% and 21%. Where the majority of CYP2C9 active compounds were predicted to be both a substrate and an inhibitor at the same time, the CYP2D6 active compounds were primarily predicted to be only inhibitors. It was demonstrated that the models could identify compound classes with a high occurrence of specific CYP activity. An overrepresentation was seen for poly-aromatic hydrocarbons (group of procarcinogens) among CYP2C9 active and mutagenic compounds compared to CYP2C9 inactive and mutagenic compounds. The mutagenicity was predicted with a QSAR model based on Ames in vitro test data.
authors.affiliation: Department of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark. sojo@food.dtu.dk
authors.forename: Svava Ósk
authors.initials: SÓ
authors.lastname: Jónsdóttir
authors.forename: Tine
authors.initials: T
authors.lastname: Ringsted
authors.forename: Nikolai G
authors.initials: NG
authors.lastname: Nikolov
authors.forename: Marianne
authors.initials: M
authors.lastname: Dybdahl
authors.forename: Eva Bay
authors.initials: EB
authors.lastname: Wedebye
authors.forename: Jay R
authors.initials: JR
authors.lastname: Niemelä
mesh_terms: D000925:Anticoagulants / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D002273:Carcinogens; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6