Studies on the metabolites difference of psoralen/isopsoralen in human and six mammalian liver microsomes in vitro by UHPLC-MS/MS

Abstract

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.

Keywords: Epoxide; Isopsoralen; Metabolism; Psoralen; Species difference.