In vitro Drug Metabolism Investigation of 7-Ethoxycoumarin in Human, Monkey, Dog and Rat Hepatocytes by High Resolution LC-MS/MS.

Drug metabolism letters Pub Date : 2018-01-01 DOI:10.2174/1872312812666180418142056

Wan-Yong Feng, Jenny Wen, Kathe Stauber

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引用次数: 5

Abstract

Background: Recently, it has been an increasing concern on the bioactivation and adverse reactions associated with consumption of herbal and nature products. 7-Ethoxycoumarin is one of coumarin family compounds, but little information is available regarding its potential reactive metabolites.

Method: 7-ethoxylcoumarin was incubated individually with human, monkey, dog and rat hepatocytes for 2 hr, metabolites were detected, identified and characterized using high resolution liquid chromagraphy - tandem mass spectrometry.

Results: Twenty-eight metabolites (M1 - M28) were detected and identified. O-deethylation, glucuronidation, sulfation, oxygenation, oxidative ring-opening, hydrogenation, glutathionation, dehydrogenation, cysteination, glucosidation, methylation, and hydrolysis were observed. At least sixteen metabolites not reported previously, were newly identified. M1 (O-deethylation, mono-oxygenation and glucuronidation), M3 (O-deethylation and glucuronidation), M5 (hydrolysis and mono-oxygenation), M14 (O-deethylation), M16 (hydrolysis), M22 (oxidative ring-opening and oxygenation) and M27 (monooxygenation) exhibited high mass spectrometric responses in human hepatocytes. M3, M5, M8, M13 (mono-oxygenation), M14, M16, M18 (O-deethylation and sulfation), M22 and M27 exhibited high mass spectrometric responses in monkey hepatocytes. M14, M16, M18, M20 (glutathionation and dehydrogenation) and M27 exhibited high mass spectrometric responses in dog hepatocytes. M1 (Odeethylation, mono-oxygenation and glucuronidation), M3, M5, M13, M14, M16, M17 (cysteination), M18, M20, and M22 exhibited high mass spectrometric responses in rat hepatocytes.

Conclusion: Most of new metabolites via oxidative ring-opening and glutathionation were identified. Species differences in metabolism of 7-ethoxylcoumarin in hepatocytes were observed. The analysis of metabolites suggests that 7-ethoxylcoumarin may undergo 3,4-epoxidation responsible for formation of glutathione and its derived cysteine conjugates, carboxylic acid and its glucuronides, glucosides and sulfate.

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高分辨率LC-MS/MS法研究7-乙氧基香豆素在人、猴、狗和大鼠肝细胞中的体外代谢

背景:近年来，人们越来越关注与食用草药和天然产品相关的生物活性和不良反应。7-乙氧基香豆素是香豆素家族化合物之一，但关于其潜在的活性代谢产物的信息很少。方法:7-乙氧基香豆素与人、猴、狗、大鼠肝细胞分别孵育2小时，采用高分辨率液相色谱-串联质谱法检测、鉴定和表征其代谢产物。结果:共检出28种代谢物(M1 ~ M28)。观察了o -去乙基化、葡萄糖醛酸化、硫酸化、氧合、氧化开环、加氢、谷胱甘肽化、脱氢、半胱氨酸化、葡萄糖苷化、甲基化和水解。至少有16种以前未报道的代谢物是新发现的。M1 (o -去乙基化、单氧化和葡萄糖醛酸化)、M3 (o -去乙基化和葡萄糖醛酸化)、M5(水解和单氧化)、M14 (o -去乙基化)、M16(水解)、M22(氧化开环和氧化)和M27(单氧化)在人肝细胞中表现出高的质谱反应。M3、M5、M8、M13(单氧)、M14、M16、M18 (o-去乙基化和磺化)、M22和M27在猴肝细胞中表现出较高的质谱反应。M14、M16、M18、M20(谷胱甘肽化和脱氢)和M27在狗肝细胞中表现出较高的质谱反应。M1(脱乙基化、单氧化和葡萄糖醛酸化)、M3、M5、M13、M14、M16、M17(半胱氨酸化)、M18、M20和M22在大鼠肝细胞中表现出高质谱反应。结论:多数新代谢产物通过氧化开环和谷胱甘肽化被鉴定出来。观察了7-乙氧基香豆素在肝细胞代谢中的物种差异。代谢产物分析表明，7-乙氧基香豆素可能发生3,4-环氧化反应，形成谷胱甘肽及其衍生的半胱氨酸缀合物、羧酸及其葡萄糖醛酸盐、糖苷和硫酸盐。

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Drug metabolism letters Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science

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期刊介绍： Drug Metabolism Letters publishes letters and research articles on major advances in all areas of drug metabolism and disposition. The emphasis is on publishing quality papers very rapidly by taking full advantage of the Internet technology both for the submission and review of manuscripts. The journal covers the following areas: In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites.