title: In vitro oxidative metabolism of cajaninstilbene Acid by human liver microsomes and hepatocytes: involvement of cytochrome p450 reaction phenotyping, inhibition, and induction studies.
abstract: Cajaninstilbene acid (CSA, 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid), an active constituent of pigeonpea leaves, an important tropical crop, is known for its clinical effects in the treatment of diabetes, hepatitis, and measles and its potential antitumor effect. In this study, the effect of the cytochrome P450 isozymes on the activity of CSA was investigated. Two hydroxylation metabolites were identified in the study. The reaction phenotype study showed that CYP3A4, CYP2C9, and CYP1A2 were the major cytochrome P450 isozymes in the metabolism of CSA. The metabolic food-drug interaction potential was also evaluated in vitro. The effect of CSA inhibition/induction of enzymatic activities of seven drug-metabolizing CYP450 isozymes in vitro was estimated by high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques. CSA showed different inhibitory effects on different isozymes. CSA reversibly inhibited CYP3A4 and CYP2C9 activities in human liver microsomes with IC50 values of 28.3 and 31.3 μM, respectively, but exhibited no inhibition activities to CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP2E1. CSA showed a weak effect on CYP450 enzymes in a time-dependent manner. CSA did not substantially induce CYP1A2, CYP2A6, CYP2B6, CYP2E1, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations up to 30 μM in primary human hepatocytes. The results of our experiments may be helpful to predict clinically significant food-drug interactions when other drugs are administered in combination with CSA.
authors.affiliation: State Engineering Laboratory of Bio-Resource Eco-Utilization and ‡Collaborative Innovation Center for Development and Utilization of Forest Resources, Northeast Forestry University , Harbin, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Hua
authors.forename: Xiao
authors.initials: X
authors.lastname: Peng
authors.forename: Shengnan
authors.initials: S
authors.lastname: Tan
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Luo
authors.forename: Yujie
authors.initials: Y
authors.lastname: Fu
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Zu
authors.forename: Hugh
authors.initials: H
authors.lastname: Smyth
mesh_terms: D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D008875:Middle Aged; D015394:Molecular Structure; D010084:Oxidation-Reduction; D012459:Salicylates / Q000737:chemistry / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: C549543:3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid; D065607:Cytochrome P-450 Enzyme Inhibitors; D012459:Salicylates; D013267:Stilbenes; D003577:Cytochrome P-450 Enzyme System
keywords: cajaninstilbene acid; food−drug interaction; human hepatocytes; human liver microsomes; recombinant human P450 enzymes