title: Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: selectivity, kinetic characterization, and molecular modeling.
abstract: Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least Ki value of 44±16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC50 values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different.
authors.affiliation: National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC; Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Lo
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Chang
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Chang
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: Yune-Fang
authors.initials: YF
authors.lastname: Ueng
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry / Q000235:genetics; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065633:Cytochrome P-450 CYP1B1; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D040681:Structural Homology, Protein
chemical_list: D001600:Berberine Alkaloids; D065609:Cytochrome P-450 CYP1A2 Inhibitors; C055785:jatrorrhizine; D001599:Berberine; D001189:Aryl Hydrocarbon Hydroxylases; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; C005413:palmatine
keywords: 7-ethoxycoumarin O-deethylation; 7-ethoxyresorufin O-deethylation; 7-methoxyresorufin O-demethylation; AHH; Berberine; CYP1B1; ECOD; EROD; MROD; P450, CYP; Selective inhibition; benzo(a)pyrene hydroxylase; cytochrome P450