Jiangsu Provincial Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
J Ethnopharmacol. 2012 Oct 31;144(1):73-81. doi: 10.1016/j.jep.2012.08.028. Epub 2012 Aug 30.
Fructus Psoraleae (FP) has been widely used to heal skin diseases as well as osteoporosis, osteomalacia, and bone fracture. There also exist many clinical reports about FP-induced hepatotoxicity associated with acute cholestatic hepatic injury. However, the FP-induced hepatotoxicity and the underlying mechanisms remain unclear.
The present study aims to determine the hepatotoxicity of FP in Sprague-Dawley (SD) rats and to investigate the underlying mechanisms.
Sprague-Dawley rats of both sexes were intragastrically administered with the EtOH extract of FP (EEFP) at doses of 1.875, 1.25 and 0.625 g/kg for 28 day. Body weight, relative liver weight, biochemical analysis, histopathology, the mRNA and protein expression of Cholesterol 7α-hydroxylase (CYP7A1), farnesoid X receptor (FXR), bile-salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), multidrug resistance-associated protein 3 (MRP3) were evaluated to study the EEFP-induced hepatotoxicity and its underlying mechanisms.
Many abnormalities were observed in the EEFP-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, increased weight of liver, and decreased concentration of bile acid in bile. The mRNA and protein expression of CYP7A1, MRP3, MRP2, BSEP increased and the expression of FXR decreased in EEFP-treated female groups; the mRNA and protein of FXR and CYP7A1 decreased and that of the others remained the same in EEFP-treated male groups.
In conclusion, we provide evidence for the first time that EEFP can induce sex-related cholestatic hepatotoxicity, and that female rats are more sensitive to EEFP-induced hepatotoxicity, which involves the destruction of the biosynthesis and transportation of bile acid. Further investigation is still needed to uncover the mechanism of the sex-dimorphic EEFP-induced hepatotoxicity.
补骨脂（FP）被广泛用于治疗皮肤病以及骨质疏松症、佝偻病和骨折。也有许多关于 FP 诱导的与急性胆汁淤积性肝损伤相关的肝毒性的临床报告。然而，FP 诱导的肝毒性及其潜在机制尚不清楚。
本研究旨在确定 FP 对 Sprague-Dawley（SD）大鼠的肝毒性，并探讨其潜在机制。
雌雄 SD 大鼠分别灌胃给予 FP 的醇提物（EEFP），剂量为 1.875、1.25 和 0.625 g/kg，连续 28 天。评估体重、相对肝重、生化分析、组织病理学、胆固醇 7α-羟化酶（CYP7A1）、法尼醇 X 受体（FXR）、胆汁盐输出泵（BSEP）、多药耐药相关蛋白 2（MRP2）和多药耐药相关蛋白 3（MRP3）的 mRNA 和蛋白表达，以研究 EEFP 诱导的肝毒性及其潜在机制。
EEFP 处理组观察到许多异常，包括体重增加和食物摄入抑制、血清生化参数改变、肝重增加和胆汁中胆汁酸浓度降低。EEFP 处理的雌性大鼠中 CYP7A1、MRP3、MRP2、BSEP 的 mRNA 和蛋白表达增加，FXR 表达减少；EEFP 处理的雄性大鼠中 FXR 和 CYP7A1 的 mRNA 和蛋白表达减少，而其他基因的表达保持不变。
总之，我们首次提供了证据，证明 EEFP 可引起与性别相关的胆汁淤积性肝毒性，雌性大鼠对 EEFP 诱导的肝毒性更敏感，涉及胆汁酸生物合成和转运的破坏。仍需要进一步研究以揭示 EEFP 诱导的性别二态性肝毒性的机制。
