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鉴定人肝微粒体中 23-羟基白桦酸代谢涉及的细胞色素 P450 同工酶。

Identification of cytochrome P450 isoenzymes involved in the metabolism of 23-hydroxybetulinic acid in human liver microsomes.

机构信息

Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.

出版信息

Pharm Biol. 2020 Dec;58(1):60-63. doi: 10.1080/13880209.2019.1701500.

DOI:10.1080/13880209.2019.1701500
PMID:31868554
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6968681/
Abstract

23-Hydroxybetulinic acid (23-HBA), a major active constituent of (Bunge) Regel (Ranunculaceae), exhibits potential antitumor activity. Its metabolism, however, has not yet been studied. This study focuses on the metabolism of 23-HBA by human liver microsomes. The metabolic kinetics of 23-HBA (0.5-100 µM) and the effects of selective CYP450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) inhibitors on metabolism of 23-HBA were evaluated in human liver microsomes incubation system and then determined by LC-MS method. The Michaelis-Menten parameters and were initially estimated by analysing Lineweaver-Burk plot. The clearance () was also calculated. The and of 23-HBA were 256.41 ± 11.20 pmol/min/mg, 11.10 ± 1.07 μM, and 23.10 ± 1.32 μL/min/mg, respectively. The metabolism of 23-HBA was significantly inhibited by furafylline (0.05 μM,  < 0.01) and ketoconazole (0.02 μM,  < 0.05). Ticlopidine (1.3 μM,  < 0.05) could inhibit the metabolism of 23-HBA, while the other inhibitors (sulfaphenazole and quinidine) showed nonsignificant inhibition on the metabolism of 23-HBA. This is the first investigation of the metabolism of 23-HBA in human liver microsomes. The study indicates that CYP1A2 and CYP3A4 are mainly involved in the metabolism of 23-HBA. Special attention should be given to the pharmacokinetic and clinical outcomes when 23-HBA was co-administrated with other compounds mainly undergoing CYP1A2/CYP3A4-mediated metabolism. Further studies are needed to evaluate the significance of this interaction and strengthen the understanding of traditional Chinese medicine.

摘要

23-羟基白桦酸（23-HBA）是毛茛科（Ranunculaceae）植物（Bunge）Regel 的主要活性成分，具有潜在的抗肿瘤活性。然而，其代谢途径尚未得到研究。本研究聚焦于人肝微粒体对 23-HBA 的代谢。在人肝微粒体孵育体系中，评估了 23-HBA（0.5-100μM）的代谢动力学以及选择性 CYP450（CYP1A2、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4）抑制剂对 23-HBA 代谢的影响，并用 LC-MS 方法进行了测定。通过分析 Lineweaver-Burk 图，初步估计了米氏常数（）和（）。清除率（）也被计算出来。23-HBA 的和分别为 256.41±11.20 pmol/min/mg、11.10±1.07μM 和 23.10±1.32μL/min/mg。23-HBA 的代谢明显受到呋喃西林（0.05μM， < 0.01）和酮康唑（0.02μM， < 0.05）的抑制。噻氯匹定（1.3μM， < 0.05）能抑制 23-HBA 的代谢，而其他抑制剂（磺胺苯砜和奎尼丁）对 23-HBA 的代谢没有明显的抑制作用。这是首次对人肝微粒体中 23-HBA 的代谢进行研究。该研究表明，CYP1A2 和 CYP3A4 主要参与 23-HBA 的代谢。当 23-HBA 与其他主要经 CYP1A2/CYP3A4 介导代谢的化合物合用时，应特别注意其药代动力学和临床结果。需要进一步研究来评估这种相互作用的意义，并加深对中药的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/81f961f118c5/IPHB_A_1701500_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/69b90b9123fa/IPHB_A_1701500_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/7ca86c67a741/IPHB_A_1701500_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/81f961f118c5/IPHB_A_1701500_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/69b90b9123fa/IPHB_A_1701500_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/7ca86c67a741/IPHB_A_1701500_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4a20/6968681/81f961f118c5/IPHB_A_1701500_F0003_B.jpg

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