Xanthotoxin, abundantly occurring in fruits, vegetables, grapefruit juice and oils, is widely used in medicine for the treatment of psoriasis and vitiligo. Xanthotoxin possesses the ability to inhibit mechanism-based cytochrome P450 (CYP450)-mediated activities in rats and mice. Furthermore, it time-dependently obstructs a number of CYP450-mediated functions in humans. CYP450 enzymes are most abundant in the liver and induce metabolic activation of numerous xenobiotic compounds. The present study aimed to identify the similarities and differences in xanthotoxin metabolism in liver microsomes of 7 mammalian species, including human liver microsomes (HLM), Rhesus monkey liver microsomes (RMLM), Cynomolgus monkey liver microsomes (CMLM), Sprague Dawley rat liver microsomes (RLM), mouse liver microsomes (MLM), Dunkin Hartley guinea pig liver microsomes (PLM) and Beagle dog liver microsomes (DLM). Ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometric analysis was used to determine the metabolites. A total of 3 metabolites were detected in RMLM, CMLM and RLM. Furthermore, two metabolites were observed in MLM, HLM, PLM and DLM. By analyzing the type and quantity of metabolites, the metabolism of xanthotoxin in MLM was indicated to be most similar to that in HLM. The metabolic transformations of xanthotoxin in the liver microsomes of the 7 species were analyzed in further detail. On the whole, the results of the present study provide a deeper understanding of the metabolic patterns of xanthotoxin in liver microsomes of different species, which may prove to be advantageous regarding the metabolic mechanisms of action of xanthotoxin. Further insight into drug metabolism with respect to different species will also aid in the selection of appropriate animal models for further research.

中文翻译：

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七种哺乳动物肝微粒体中花椒毒素代谢物的差异。


花椒毒素大量存在于水果、蔬菜、柚子汁和油中，广泛用于治疗牛皮癣和白癜风的药物中。 Xanthotoxin 能够抑制大鼠和小鼠中基于机制的细胞色素 P450 (CYP450) 介导的活性。此外，它会随着时间的推移阻碍人体中许多 CYP450 介导的功能。 CYP450 酶在肝脏中最为丰富，可诱导多种外源化合物的代谢激活。本研究旨在鉴定7种哺乳动物肝微粒体中黄毒素代谢的异同，包括人肝微粒体（HLM）、恒河猴肝微粒体（RMLM）、食蟹猴肝微粒体（CMLM）、斯普拉道利大鼠肝微粒体(RLM)、小鼠肝微粒体 (MLM)、Dunkin Hartley 豚鼠肝微粒体 (PLM) 和比格犬肝微粒体 (DLM)。使用超高效液相色谱/四极杆飞行时间质谱分析来测定代谢物。 RMLM、CMLM和RLM中总共检测到3种代谢物。此外，在 MLM、HLM、PLM 和 DLM 中观察到两种代谢物。通过分析代谢物的种类和数量，MLM中的黄毒素代谢与HLM中的代谢最为相似。进一步详细分析了 7 个物种肝微粒体中花椒毒素的代谢转化。总的来说，本研究的结果使人们对不同物种肝微粒体中花椒毒素的代谢模式有了更深入的了解，这可能有利于花椒毒素的代谢作用机制的研究。 进一步了解不同物种的药物代谢也将有助于选择合适的动物模型进行进一步研究。