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采用高分辨率液相色谱-串联质谱法对人、猴、犬和大鼠肝细胞中7-乙氧基香豆素的体外药物代谢研究

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

作者信息

Feng Wan-Yong, Wen Jenny, Stauber Kathe

机构信息

Drug Metabolism and Pharmacokinetics, Dart NeuroScience, San Diego, CA 92131, United States.

出版信息

Drug Metab Lett. 2018;12(1):33-53. doi: 10.2174/1872312812666180418142056.

DOI:10.2174/1872312812666180418142056
PMID:29669508
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6416465/
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.

摘要

背景

近年来，与食用草药和天然产物相关的生物活化及不良反应日益受到关注。7-乙氧基香豆素是香豆素家族化合物之一，但关于其潜在反应性代谢物的信息却很少。

方法

将7-乙氧基香豆素分别与人、猴、犬和大鼠的肝细胞孵育2小时，使用高分辨率液相色谱-串联质谱法检测、鉴定和表征代谢物。

结果

检测并鉴定出28种代谢物（M1 - M28）。观察到了O-去乙基化、葡萄糖醛酸化、硫酸化、氧化、氧化开环、氢化、谷胱甘肽化、脱氢、半胱氨酸化、葡萄糖苷化、甲基化和水解反应。新鉴定出至少16种以前未报道的代谢物。M1（O-去乙基化、单加氧和葡萄糖醛酸化）、M3（O-去乙基化和葡萄糖醛酸化）、M5（水解和单加氧）、M14（O-去乙基化）、M16（水解）、M22（氧化开环和氧化）和M27（单加氧）在人肝细胞中表现出较高的质谱响应。M3、M5、M8、M13（单加氧）、M14、M16、M18（O-去乙基化和硫酸化）、M22和M27在猴肝细胞中表现出较高的质谱响应。M14、M16、M18、M20（谷胱甘肽化和脱氢）和M27在犬肝细胞中表现出较高的质谱响应。M1（O-去乙基化、单加氧和葡萄糖醛酸化）、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较高的质谱响应。

结论

鉴定出了大多数通过氧化开环和谷胱甘肽化产生的新代谢物。观察到了7-乙氧基香豆素在肝细胞中代谢的种属差异。代谢物分析表明，7-乙氧基香豆素可能会发生3,4-环氧化反应，从而导致谷胱甘肽及其衍生的半胱氨酸共轭物、羧酸及其葡萄糖醛酸苷、葡萄糖苷和硫酸盐的形成。

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