Shi Xianbao, Zhang Gang, Mackie Brianna, Yang Shuman, Wang Jian, Shan Lina
Department of Pharmacy, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China.
Department of Pharmacy, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, China; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Sep 1;1029-1030:145-156. doi: 10.1016/j.jchromb.2016.06.031. Epub 2016 Jun 30.
Psoralidin has shown a variety of biological and pharmacological activities such as anti-tumor anti-oxidant, anti-bacterial, anti-depressant and anti-inflammatory activities. Herein, we reported the metabolism of psoralidin among different species and its inhibitory effect against UGTs and CYP450s. Liquid chromatography was used to investigate the inhibitory activity of psoralidin against ten different UGTs and eight distinct CYP450 isoforms. In addition, we characterized the CYP450 isoforms involved in the psoralidin metabolism on the basis of chemical inhibition studies and screening assays with recombinant human cytochrome P450s. In vitro metabolic profiles and metabolites of psoralidin from varying liver microsomes obtained from human (HLMs), monkey (MLMs), rat (RLMs), dog (DLMs), minipig (PLMs) and rabbit (RAMs) were determined by LC-MS/MS. In vivo pharmacokinetic profiles were investigated by injecting psoralidin (2mg/kg) into the tail vein of Wistar rats. Molecular modeling studies were carried out in order to assess the binding profile and recognition motif between psoralidin and the enzymes. Psoralidin showed potent and noncompetitive inhibition against UGT1A1, UGT1A7, CYP1A2 and CYP2C8 with IC50 values of 6.12, 0.38, 1.81, 0.28μM, respectively. The metabolism of psoraldin exhibited significant differences among humans, monkeys, dogs, minipigs, rabbits and rats; however, monkeys showed the highest similarity to humans. Furthermore, eleven metabolites were observed among these species and their structures were characterized by LC-MS/MS. CYP2C19 played a key role in the metabolism of psorslidin in human liver microsomes. These findings could be used to advance the understanding of psoralidin.
补骨脂定已显示出多种生物学和药理活性，如抗肿瘤、抗氧化、抗菌、抗抑郁和抗炎活性。在此，我们报道了补骨脂定在不同物种中的代谢及其对尿苷二磷酸葡萄糖醛酸转移酶（UGTs）和细胞色素P450（CYP450s）的抑制作用。采用液相色谱法研究补骨脂定对10种不同UGTs和8种不同CYP450同工酶的抑制活性。此外，我们基于化学抑制研究和重组人细胞色素P450的筛选试验，对参与补骨脂定代谢的CYP450同工酶进行了表征。通过液相色谱-串联质谱（LC-MS/MS）测定了来自人（HLMs）、猴（MLMs）、大鼠（RLMs）、狗（DLMs）、小型猪（PLMs）和兔（RAMs）的不同肝微粒体中补骨脂定的体外代谢谱和代谢产物。通过将补骨脂定（2mg/kg）注射到Wistar大鼠尾静脉中研究其体内药代动力学谱。进行分子模拟研究以评估补骨脂定与酶之间的结合谱和识别基序。补骨脂定对UGT1A1、UGT1A7、CYP1A2和CYP2C8表现出强效非竞争性抑制，IC50值分别为6.12、0.38、1.81、0.28μM。补骨脂定的代谢在人、猴、狗、小型猪、兔和大鼠之间存在显著差异；然而，猴与人表现出最高的相似性。此外，在这些物种中观察到了11种代谢产物，其结构通过LC-MS/MS进行了表征。CYP2C19在人肝微粒体中补骨脂定的代谢中起关键作用。这些发现有助于增进对补骨脂定的理解。
