{"title":"Metabolite profiling and identification of enzymes responsible for the metabolism of hirsutine, a major alkaloid from <i>Uncaria rhynchophylla</i>.","authors":"Yiqing Guo, Huanhuan Lv, Jing Lv, Zenghong Jiang","doi":"10.1080/00498254.2023.2269417","DOIUrl":null,"url":null,"abstract":"<p><p>The <i>in vitro</i> metabolism of hirsutine was determined using liver microsomes and human recombinant cytochrome P450 enzymes. Under the current conditions, a total of 14 phase I metabolites were tentatively identified.Ketoconazole showed significant inhibitory effect on the metabolism of hirsutine. Human recombinant cytochrome P450 enzyme analysis revealed that metabolism of hirsutine was mainly catalysed by CYP3A4.Our data revealed that hirsutine was metabolised <i>via</i> mono-oxygenation, di-oxygenation, <i>N</i>-oxygenation, dehydrogenation, demethylation and hydrolysis.In glutathione (GSH)-supplemented liver microsomes, four GSH adducts were identified. Hirsutine underwent facile P450-mediated metabolic activation, forming reactive 3-methyleneindolenine and iminoquinone intermediates.This study provided valuable information on the metabolic fates of hirsutine in liver microsomes, which would aid in understanding the hepatotoxicity caused by hirsutine or hirsutine-containing herb preparation.</p>","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"474-483"},"PeriodicalIF":1.3000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Xenobiotica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/00498254.2023.2269417","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/11/3 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
The in vitro metabolism of hirsutine was determined using liver microsomes and human recombinant cytochrome P450 enzymes. Under the current conditions, a total of 14 phase I metabolites were tentatively identified.Ketoconazole showed significant inhibitory effect on the metabolism of hirsutine. Human recombinant cytochrome P450 enzyme analysis revealed that metabolism of hirsutine was mainly catalysed by CYP3A4.Our data revealed that hirsutine was metabolised via mono-oxygenation, di-oxygenation, N-oxygenation, dehydrogenation, demethylation and hydrolysis.In glutathione (GSH)-supplemented liver microsomes, four GSH adducts were identified. Hirsutine underwent facile P450-mediated metabolic activation, forming reactive 3-methyleneindolenine and iminoquinone intermediates.This study provided valuable information on the metabolic fates of hirsutine in liver microsomes, which would aid in understanding the hepatotoxicity caused by hirsutine or hirsutine-containing herb preparation.
期刊介绍：
Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology
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