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首页> 外文期刊>Journal of mass spectrometry: JMS >Characterization of stable and reactive metabolites of piperine formed on incubation with human liver microsomes
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Characterization of stable and reactive metabolites of piperine formed on incubation with human liver microsomes

机译：用人肝微粒体孵育形成哌啶稳定和活性代谢物的特征

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摘要

Black pepper, though commonly employed as a spice, has many medicinal properties. It consists of volatile oils, alkaloids, pungent resins, etc., of which piperine is a major constituent. Though safe at low doses, piperine causes alteration in the activity of drug metabolising enzymes and transporters at high dose and is known to precipitate liver toxicity. It has a potential to form reactive metabolite(s) (RM) owing to the presence of structural alerts, such as methylenedioxyphenyl (MDP), alpha, beta-unsaturated carbonyl group (Michael acceptor), and piperidine. The present study was designed to detect and characterize stable and RM(s) of piperine formed on in vitro incubation with human liver microsomes. The investigation of RMs was done with the aid of trapping agents, viz, glutathione (GSH) and N-acetylcysteine (NAC). The samples were analysed by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC-HRMS) using Thermo Scientific Q Exactive Plus Orbitrap. Full scan MS followed by data-dependent MS2 (Full MS-ddMS(2)) mode was used to establish mass spectrometric fragmentation pathways of protonated piperine and its metabolites. In total, four stable metabolites and their isomers (M1a-c, M2a-b, M3a-c, and M4a-b) were detected. Their formation involved removal of carbon (3, M1a-c), hydroxylation (2, M2a-b), hydroxylation with hydrogenation (3, M3a-c), and dehydrogenation (2, M4a-b). Out of these metabolites, M1, M2, and M3 are reported earlier in the literature, but their isomers and two M4 variants are novel. In addition, six novel conjugates of RMs, including three GSH conjugates of m/z 579 and three NAC conjugates of m/z 435, were also observed.
机译：黑胡椒虽然通常用作香料，但具有许多药用特性。它由哌啶油，生物碱，刺激性树脂等组成，其中哌啶是主要的组成部分。虽然以低剂量安全，但哌啶导致高剂量的药物代谢酶和转运蛋白活动的变化，并且已知沉淀肝毒性。由于存在结构警报，例如亚甲基二苯基（MDP），α，β-不饱和羰基（Michael受体）和哌啶，它具有可能形成反应性代谢物（RM）。本研究设计用于检测和表征在与人肝微粒体的体外孵育中形成的稳定和RM的哌啶。借助于诱捕剂，Viz，谷胱甘肽（GSH）和N-乙酰半胱氨酸（NAC），对RMS进行研究。通过使用热科学Q辐射加上露仓，通过超高效液相色谱法分析样品的超高效液相色谱分析了高分辨率质谱（UHPLC-HRMS）。全扫描MS随后是数据相关的MS2（全MS-DDMS（2））模式用于建立质子化哌啶的质谱分段途径及其代谢物。总共，检测四种稳定的代谢物及其异构体（M1A-C，M2A-B，M3A-C和M4A-B）。它们的形成涉及除去碳（3，M1A-C），羟基化（2，M2A-B），用氢化（3，M3A-C）和脱氢（2，M4A-B）的羟基化。在这些代谢物中，在文献中提前报告了M1，M2和M3，但它们的异构体和两种M4变异是新颖的。此外，还观察到，还观察到六种RM的六种新缀合物，包括M / Z 579的三种GSH缀合物和M / Z 435的三种NAC缀合物。

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