title: Comparison of the in vitro metabolism of psoralidin among different species and characterization of its inhibitory effect against UDP- glucuronosyltransferase (UGT) or cytochrome p450 (CYP450) enzymes.
abstract: Psoralidin has shown a variety of biological and pharmacological activities such as anti-tumor anti-oxidant, anti-bacterial, anti-depressant and anti-inflammatory activities. Herein, we reported the metabolism of psoralidin among different species and its inhibitory effect against UGTs and CYP450s. Liquid chromatography was used to investigate the inhibitory activity of psoralidin against ten different UGTs and eight distinct CYP450 isoforms. In addition, we characterized the CYP450 isoforms involved in the psoralidin metabolism on the basis of chemical inhibition studies and screening assays with recombinant human cytochrome P450s. In vitro metabolic profiles and metabolites of psoralidin from varying liver microsomes obtained from human (HLMs), monkey (MLMs), rat (RLMs), dog (DLMs), minipig (PLMs) and rabbit (RAMs) were determined by LC-MS/MS. In vivo pharmacokinetic profiles were investigated by injecting psoralidin (2mg/kg) into the tail vein of Wistar rats. Molecular modeling studies were carried out in order to assess the binding profile and recognition motif between psoralidin and the enzymes. Psoralidin showed potent and noncompetitive inhibition against UGT1A1, UGT1A7, CYP1A2 and CYP2C8 with IC50 values of 6.12, 0.38, 1.81, 0.28μM, respectively. The metabolism of psoraldin exhibited significant differences among humans, monkeys, dogs, minipigs, rabbits and rats; however, monkeys showed the highest similarity to humans. Furthermore, eleven metabolites were observed among these species and their structures were characterized by LC-MS/MS. CYP2C19 played a key role in the metabolism of psorslidin in human liver microsomes. These findings could be used to advance the understanding of psoralidin.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China.
authors.forename: Xianbao
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Mackie
authors.affiliation: Department of Internal Medicine/Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Shuman
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China. Electronic address: shanlina123@163.com.
authors.forename: Lina
authors.initials: L
authors.lastname: Shan
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D002853:Chromatography, Liquid; D003374:Coumarins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature; D053719:Tandem Mass Spectrometry; D000099148:UGT1A1 Enzyme
chemical_list: D001572:Benzofurans; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004365:Drugs, Chinese Herbal; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme; C524630:UGT1A7 protein, human; C102768:psoralidin
keywords: Cytochrome P450; Drug-drug interactions; Glucuronosyltransferase (UGT); LC–MS/MS; Psoralidin