Abstract：
Graveoline is a biologically active ingredient extracted from Ruta graveolens. Current work aimed at investigating in vitro metabolism of graveoline using rat or human liver microsomes and hepatocytes. Graveoline (20 μM) was incubated with nicotinamide adenine dinucleotide phosphate-supplemented rat and human liver microsomes as well as hepatocytes. LC coupled to a photo diode array detector and quadrupole/time-of-flight tandem mass spectrometry was used to detect and identify the metabolites. The structures of the metabolites were identified by accurate mass, elemental composition, and indicative fragment ions. A total of 12 metabolites, comprising 6 phase I and 6 phase II metabolites, were obtained. The metabolic pathways included demethylenation, demethylation, hydroxylation, glucuronidation, and glutathion conjugation. The metabolite (M10) produced by opening the ring of the methylenedioxyphenyl moiety was detected as the most abundant in both liver microsomes and hepatocytes, mainly catalyzed by CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5. This study provides valuable information on the in vitro metabolism of graveoline, which is indispensable for further development and safety evaluation of this compound.
摘要：
Graveoline是从Rutagraveolens中提取的生物活性成分。目前的工作旨在研究使用大鼠或人肝微粒体和肝细胞的体外代谢。将Graveoline（20μM）与补充有烟酰胺腺嘌呤二核苷酸磷酸的大鼠和人肝微粒体以及肝细胞一起孵育。使用与光电二极管阵列检测器和四极杆/飞行时间串联质谱法耦合的LC来检测和鉴定代谢物。代谢物的结构通过准确的质量鉴定，元素组成,和指示性碎片离子。共有12种代谢物，包含6个I相和6个II相代谢物，已获得。代谢途径包括脱乙烯，去甲基化,羟基化,葡糖醛酸化，和谷胱甘肽缀合。通过打开亚甲二氧基苯基部分的环产生的代谢物（M10）在肝微粒体和肝细胞中均被检测为最丰富的，主要由CYP1A2、2C8、2C9、2C19、2D6、3A4和3A5催化。本研究为Graveoline的体外代谢提供了有价值的信息，这对于该化合物的进一步开发和安全性评价是必不可少的。
