title: Enzyme kinetic and molecular docking studies on the metabolic interactions of 1-hydroxy-2,3,5-trimethoxy-xanthone, isolated from Halenia elliptica D. Don, with model probe substrates of human cytochrome P450 enzymes.
abstract: Halenia elliptica D. Don is a Tibetan herb and medicinal preparations containing Halenia elliptica have been commonly used for the treatment of hepatitis B virus infection in China. The metabolism of 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1) to its metabolites is mediated through cytochrome P450 enzymes. This study aimed to investigate the herb-drug interaction potential of HM-1 by studying its effects on the metabolism of model probe substrates of five major CYP450 isoforms in human liver microsomes. HM-1 showed moderate inhibitory effects on CYP1A2 (IC₅₀ = 1.06 μM) and CYP2C9 (IC₅₀ = 3.89 μM), minimal inhibition on CYP3A4 (IC₂₀ = 11.94 μM), but no inhibition on model CYP2D6 (dextromethorphan) and CYP2E1 (chlorzoxazone) probe substrates. Inhibition kinetic studies showed that the K(i) values of HM-1 on CYP1A2, CYP2C9 and CYP3A4 were 5.12 μM, 2.00 μM and 95.03 μM, respectively. HM-1 competitively inhibited testosterone 6β-hydroxylation (CYP3A4) but displayed mixed type inhibitions for phenacetin O-deethylation (CYP1A2) and tolbutamide 4-hydroxylation (CYP2C9). Molecular docking study confirmed the inhibition modes of HM-1 on these human CYP isoforms.
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, China.
authors: Ru
authors: R
authors: Feng
authors: Xuelin
authors: X
authors: Zhou
authors: Penelope M Y
authors: PM
authors: Or
authors: Jing-Yi
authors: JY
authors: Ma
authors: Xiang-Shan
authors: XS
authors: Tan
authors: Jie
authors: J
authors: Fu
authors: Chao
authors: C
authors: Ma
authors: Jian-Gong
authors: JG
authors: Shi
authors: Chun-Tao
authors: CT
authors: Che
authors: Yan
authors: Y
authors: Wang
authors: John H K
authors: JH
authors: Yeung
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D029965:Gentianaceae / Q000737:chemistry*; D041743:Herb-Drug Interactions; D006801:Humans; D010615:Phenacetin / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D013739:Testosterone / Q000378:metabolism; D014044:Tolbutamide / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: C478004:1-hydroxy-2,3,5-trimethoxyxanthone; D010936:Plant Extracts; D044004:Xanthones; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D010615:Phenacetin