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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7种哺乳动物肝微粒体中黄嘌呤毒素代谢产物的差异。

花椒毒素存在于水果，蔬菜，葡萄柚汁和油中，广泛用于治疗牛皮癣和白癜风。黄嘌呤毒素具有抑制大鼠和小鼠中基于机制的细胞色素P450（CYP450）介导的活性的能力。此外，它在时间上阻碍人类中许多CYP450介导的功能。CYP450酶在肝脏中含量最高，可诱导多种异生物素化合物的代谢活化。本研究旨在确定7种哺乳动物的肝微粒体中黄嘌呤毒素代谢的异同，包括人肝微粒体（HLM），恒河猴肝微粒体（RMLM），食蟹猴肝微粒体（CMLM），Sprague Dawley大鼠肝微粒体（RLM），小鼠肝微粒体（MLM），Dunkin Hartley豚鼠肝微粒体（PLM）和Beagle狗肝微粒体（DLM）。使用超高效液相色谱/四极杆飞行时间质谱分析法测定代谢物。在RMLM，CMLM和RLM中共检测到3种代谢物。此外，在MLM，HLM，PLM和DLM中观察到两种代谢物。通过分析代谢物的类型和数量，表明黄嘌呤毒素在MLM中的代谢与HLM最相似。黄嘌呤毒素在7种物种的肝微粒体中的代谢转化进行了更详细的分析。总体而言，本研究的结果提供了对不同种类肝微粒体中黄嘌呤毒素代谢模式的更深入的了解，对于黄嘌呤毒素的代谢作用机理，这可能被证明是有利的。进一步了解有关不同物种的药物代谢也将有助于选择合适的动物模型以进行进一步研究。