With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 μM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

中文翻译：

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补骨脂素和异补骨脂素是补骨脂中的两种类雌激素天然产物，通过激活 ERK1/2 诱导胆汁淤积


随着口服避孕药和雌激素替代治疗的增加，雌激素引起的胆汁淤积（EC）的发生率呈上升趋势。补骨脂素（P）和异补骨脂素（IP）是补骨脂中的主要生物活性成分，其类雌激素活性已被认识到。最近的研究还报道 ERK1/2 在小鼠 EC 中发挥着关键作用。本研究旨在探讨P和IP是否诱导EC并揭示具体机制。结果发现，80 μM 的 P 和 IP 增加了斑马鱼幼虫中 esr1、cyp19a1b 的表达以及 E2 和 VTG 的水平。依西美坦 (Exe) 是一种芳香酶拮抗剂，可阻断 P 和 IP 的雌激素样活性。同时，P和IP诱导斑马鱼幼虫产生胆汁淤积性肝毒性，增加肝脏荧光面积和胆汁流量抑制率。进一步的机制分析表明，P和IP显着降低胆汁酸（BAs）合成基因cyp7a1和cyp8b1、BAs转运基因abcb11b和slc10a1以及BAs受体基因nr1h4和nr0b2a的表达。此外，P和IP通过增加ERK1/2的磷酸化水平引起EC。 ERK1/2拮抗剂GDC0994和Exe对胆汁淤积性肝损伤均显示出显着的挽救作用。总之，我们全面研究了P和IP诱导EC的具体机制，并推测ERK1/2可能是植物雌激素诱导EC的重要治疗靶点。