title: Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs.
abstract: The three purified herbal compounds tetrahydropalmatine (Tet), neferine and berberine (Ber) were explored in vitro for basic inhibition mechanisms towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Phenacetin, dextromethorphan and testosterone, respectively, were used as CYP1A2, CYP2D6 and CYP3A4 substrates, and their metabolites were determined by validated HPLC methodologies. Positive inhibition controls were used. Mechanism-based (irreversible) inhibition was assessed by time-dependent and nicotinamide adenine dinucleotide phosphate-dependent and reversible inhibition by Lineweaver-Burk plot assessments. Inhibition mechanisms were also assessed by computerized interaction prediction by using the Discovery Studio CDOCKER software (Accelrys, San Diego, CA, USA). Tetrahydropalmatine showed a mechanism-based inhibition of both CYP1A2 and CYP2D6, and Ber of CYP2D6. Neferine and Ber both showed a nonmechanistic inhibition of CYP1A2. All compounds showed a similar and significant mechanism-based inhibition of CYP3A4. Tetrahydropalmatine and Ber demonstrated both reversible and irreversible inhibition of CYP2D6 and CYP3A4. Tetrahydropalmatine and Ber displayed H-bond and several Pi-bond connections with specific amino acid residues of CYP1A2, CYP2D6 and CYP3A4, giving further knowledge to the identified reversible and irreversible herb-drug interactions. Tetrahydropalmatine and Ber should be considered for herb-drug interactions in clinical therapy until relevant clinical studies are available.
authors: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.|Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors: Yong
authors: Y
authors: Zhao
authors: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors: Bent Håvard
authors: BH
authors: Hellum
authors: Institute of Chinese Materia Medica (ICMM), China Academy of Chinese Medical Sciences (CACMS), Beijing, 100700, China.
authors: Aihua
authors: A
authors: Liang
authors: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
authors: Odd Georg
authors: OG
authors: Nilsen
mesh_terms: D044182:Benzylisoquinolines / Q000302:isolation & purification / Q000494:pharmacology*; D001599:Berberine / Q000302:isolation & purification / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D010936:Plant Extracts / Q000494:pharmacology*
chemical_list: D044182:Benzylisoquinolines; D001600:Berberine Alkaloids; D065607:Cytochrome P-450 Enzyme Inhibitors; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D001599:Berberine; C057222:neferine; C014215:tetrahydropalmatine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP inhibition; inhibitory mechanisms; purified herbal compounds