Combination of molecular docking and liver transcription sequencing analysis for the evaluation of salt-processed psoraleae fructus-induced hepatotoxicity in ovariectomized mice

Salt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, SPF-associated hepatotoxicity is a known health hazard. Cholestasis is often associated with SPF-induced hepatotoxicity. Notably, clinical liver injury is a common side effe...

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Published in:Journal of ethnopharmacology 2022-04, Vol.288, p.114955-114955, Article 114955
Main Authors: Wu, Yu, Min, LingTian, Xu, Yan, Liu, Heng, Zhou, Nong, Hua, ZhengYing, Mei, ChunMei, Jiang, Ziyu, Li, Weidong
Format: Article
Language:English
Subjects:
Animals
Bile Acids and Salts - metabolism
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - pathology
Cholestasis - chemically induced
Cholestasis - pathology
Cholestatic liver injury
Disease Models, Animal
Dose-Response Relationship, Drug
Estrogens - deficiency
Female
Fruit
FXR-SULT1E1 signaling
Hepatocytes - drug effects
Hepatocytes - pathology
Mice
Mice, Inbred ICR
Molecular Docking Simulation
Ovariectomized murine model
Ovariectomy
Patient Acuity
Plant Extracts - administration & dosage
Plant Extracts - toxicity
Psoralea - chemistry
Salt-processed psoraleae fructus
Salts
Transcription, Genetic
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Summary:Salt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, SPF-associated hepatotoxicity is a known health hazard. Cholestasis is often associated with SPF-induced hepatotoxicity. Notably, clinical liver injury is a common side effect of SPF in the treatment of osteoporosis; however, the exact mechanism underlying this phenomenon is unclear. Aim of the study: To evaluate SPF-induced hepatotoxicity in an ovariectomized murine model of estrogen deficiency and examine the mechanisms underlying this process. To explore the molecular mechanism of SPF-induced cholestatic liver injury, different concentrations of SPF (5 and 10 g/kg) were intragastrically administered to ovariectomized and non-ovariectomized female ICR mice for 30 days. SPF-treated mice showed noticeably swollen hepatocytes, dilated bile ducts, and elevated levels of serum biochemical markers. Compared to ovariectomized mice, these changes were more prominent in non-ovariectomized mice. According to the sequence data, a total of 6689 mRNAs were identified. Compared with the control group, 1814 differentially expressed mRNAs were identified in the group treated with high SPF doses (SPHD), including 939 upregulated and 875 downregulated mRNAs. Molecular docking and Western blot experiments showed that liver injury was closely related to the estrogen levels. Compared with the negative control group, the expression levels of FXR, Mrp2, CYP7a1, BSEP, SULT1E1, HNF4a, and Nrf2 decreased in the estradiol-treated (E2), low-dose SPF-treated (SPLD), and SPHD groups. Interestingly, the expression levels of FXR, CYP7a1, SULT1E1, and HNF4α were significantly higher in the ovariectomized groups than in the non-ovariectomized groups (#P 
ISSN:0378-8741
1872-7573
DOI:10.1016/j.jep.2021.114955