Yang Aihong, Chen Junxiu, Ma Yetao, Wang Lili, Fan Yaowen, He Xin
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, PR China; Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, 300193, PR China.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, PR China.
J Pharm Biomed Anal. 2017 Jul 15;141:200-209. doi: 10.1016/j.jpba.2017.04.026. Epub 2017 Apr 20.
Psoralen and isopsoralen are found in many fruits, vegetables and traditional Chinese medicines (TCM), such as Ficus carica L., Celery, Fructus Psoraleae etc. Modern pharmacological studies found that psoralen and isopsoralen can show estrogen-like activity, antitumor, and antibacterial activities etc. However, some research results also show some liver damage associated with the use of psoralen/isopsoralen or related medicines in human. Many studies focus on the pharmacological activities of psoralen/isopsoralen, while it is important to choose the suitable pharmacological models which are relevant to human in drug metabolism and pharmacokinetic process. The aim of this study is to identify the metabolites of psoralen/isopsoralen by human and six mammalian liver microsomes, and compare the metabolites difference of different species. Psoralen/isopsoralen are metabolized by liver microsomes of different animals to form five and seven metabolites, respectively. The metabolism of psoralen/isopsoralen undergoes hydroxylation, hydrogenation and hydrolysis, and oxidation of the furan ring to generate a furanoepoxide or γ-ketoenal intermediate. Furanoepoxide then forms a dihydrodiol, while γ-ketoenal forms 6-(7-hydroxycoumaryl)-acetic acid (in psoralen)/8-(7-hydroxycoumaryl)-acetic acid (in isopsoralen). By comparing the types of metabolites in the seven liver microsomes, it shows that the metabolic behaviors of psoralen by Beagle dog is most relevant to human, while the metabolic behaviors of isopsoralen by Sprague-Dawley rat is most similar to human. By comparing the relative amounts of the main metabolites, it shows that the metabolic capabilities of Sprague-Dawley rat and Rhesus monkey for psoralen are most similar to human, while the metabolic capabilities of Mouse, Dunkin-Hartley guinea pig, Sprague-Dawley rat, and human for isopsoralen are similar. Furthermore, the results show that the metabolic capability of human for psoralen and isopsoralen are weaker than other mammal species. The results of this work are useful for studying the metabolism mechanism of psoralen/isopsolaren, and choosing the most relevant animal species for investigation of psoralen/isopsolaren from experimental animals to human.
补骨脂素和异补骨脂素存在于许多水果、蔬菜和中药中，如无花果、芹菜、补骨脂等。现代药理学研究发现，补骨脂素和异补骨脂素具有雌激素样活性、抗肿瘤和抗菌活性等。然而，一些研究结果也表明，人类使用补骨脂素/异补骨脂素或相关药物会导致一些肝损伤。许多研究集中在补骨脂素/异补骨脂素的药理活性上，而在药物代谢和药代动力学过程中选择与人类相关的合适药理模型很重要。本研究的目的是通过人及六种哺乳动物肝微粒体鉴定补骨脂素/异补骨脂素的代谢产物，并比较不同物种代谢产物的差异。补骨脂素/异补骨脂素分别被不同动物的肝微粒体代谢形成五种和七种代谢产物。补骨脂素/异补骨脂素的代谢经历羟基化、氢化和水解，以及呋喃环的氧化以生成呋喃环氧或γ-酮烯醛中间体。呋喃环氧随后形成二氢二醇，而γ-酮烯醛形成6-(7-羟基香豆基)-乙酸（补骨脂素中）/8-(7-羟基香豆基)-乙酸（异补骨脂素中）。通过比较七种肝微粒体中的代谢产物类型，结果表明比格犬对补骨脂素的代谢行为与人类最相关，而斯普拉格-道利大鼠对异补骨脂素的代谢行为与人类最相似。通过比较主要代谢产物的相对量，结果表明斯普拉格-道利大鼠和恒河猴对补骨脂素的代谢能力与人类最相似，而小鼠、邓金-哈特利豚鼠、斯普拉格-道利大鼠和人类对异补骨脂素的代谢能力相似。此外，结果表明人类对补骨脂素和异补骨脂素的代谢能力弱于其他哺乳动物物种。这项工作的结果有助于研究补骨脂素/异补骨脂素的代谢机制，并从实验动物到人类选择最相关的动物物种来研究补骨脂素/异补骨脂素。
