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

Wu, Yu; Min, Lingtian; Xu, Yan; Liu, Heng; Zhou, Nong; Hua, Zhengying; Mei, ChunMei; Jiang, Ziyu; Li, Weidong

doi:10.1016/j.jep.2021.114955

Cited by 8 publications

(3 citation statements)

References 37 publications

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“…FXR is also reported to down‐regulate the expression of other SULT enzymes such as SULT1E1, the primary enzyme responsible for estrogen sulfonation and inactivation. As abnormal bile acid and estrogen status have been demonstrated to be usually associated with liver disease (Liu et al, 2018; Rizzo et al, 2005; Wu et al, 2022), dysregulation of FXR activity and transcriptional pathways could be a key determinant in the development of liver‐related disease.…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter

Dou

Pei

et al. 2023

Chem Biol Drug Des

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Human sulfotransferases 1A3 (SULT1A3) has received particular interest, due to their functions of catalyzing the sulfonation of numerous phenolic substrates, including bioactive endogenous molecules and therapeutic agents. However, the regulation of SULT1A3 expression and the underlying mechanism remain unclear. Here, we aimed to investigate the regulation effects of bile acid‐activated farnesoid X receptor (FXR) on SULT1A3 expression, and to shed light on the mechanism thereof. Our results demonstrated that FXR agonists (CDCA and GW4064) significantly inhibit the expression of SULT1A3 at mRNA and protein levels. In addition, overexpression of FXR led to decrease in SULT1A3 expression and knockdown of FXR significantly induced the expression of SULT1A3 in protein and mRNA levels, confirming that FXR expression manifestly showed negative regulatory effect on basal SULT1A3 expression. Furthermore, a combination of luciferase reporter gene and CHIP assays showed that FXR repressed SULT1A3 transcription through direct binding to the region at base pair positions −664 to −654. In conclusion, this study for the first time confirmed FXR was a negative transcriptional regulator of human SULT1A3 enzyme.

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Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter

Dou

Pei

et al. 2023

Chem Biol Drug Des

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“…Traditional Chinese medicines (TCMs) are highly processed herbs. Many processing methods have been developed for processing herbs, such as stir‐frying (Zhuang et al, 2018), steaming (Zhu et al, 2016), wine‐sautéing (Huang et al, 2014), salt‐processing (Wu et al, 2022), among others. These methods are designed to meet certain clinical requirements.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of the liver‐protective effects of raw and stir‐fried semen of Hovenia dulcis in rats via gas chromatography–mass spectrometry–based serum metabolomic profiling and chemometrics

Zhu

et al. 2023

Biomedical Chromatography

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In this study, we used a serum metabolomics methodology based on GC coupled with MS (GC–MS) to investigate the liver‐protective effects of raw and stir‐fried semen of Hovenia dulcis in rats models of carbon tetrachloride–induced liver injury. Multivariate statistical analysis, such as principal component analysis and orthogonal partial least squares discriminant analysis, were performed to examine changes in the metabolic state of rats with carbon tetrachloride–induced liver injury, as well as the recovery pattern of rats pretreated with the raw and stir‐fried semen of H. dulcis. Liver tissues were subjected to histopathological examination. A total of 47 biomarkers were predicted to contribute to the dynamic pathological processes in the liver injury, such as phenylalanine, glutamic acid, glycine, arachidonic acid and linoleic acid. Further analysis revealed that pathways associated with phenylalanine, tyrosine and tryptophan biosynthesis, and linoleic acid metabolism were altered in the injured liver, and that pretreatment with raw and stir‐fried semen of H. dulcis abolished the changes in the aforementioned metabolic pathways.

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“…Unfortunately, at the same time, these two components are also suspected to be the predominantly hepatotoxic ingredients (Wang et al, 2019; Yu et al, 2019; Zhang et al, 2021). Multiple mechanisms correlated psoralen and isopsoralen‐induced hepatotoxicity have been reported, such as obstructed bile acid excretion (Wang et al, 2019), disordered lipid metabolism (Zhang et al, 2019), impaired liver regeneration (Zhou et al, 2018), uneven estrogen levels (Wu et al, 2022), imbalanced endoplasmic reticulum stress (Yu et al, 2021), and energy metabolism (Xia et al, 2018), but these remain controversial. Therefore, revealing the underlying mechanism of psoralen/isopsoralen‐induced hepatotoxicity is a feasible strategy to deal with the liver injury of PF and related preparations.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

Zhang

Song

Zhao

et al. 2022

Phytotherapy Research

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Psoralen and isopsoralen are the pharmacologically important but hepatotoxic components in Psoraleae Fructus. The purpose of this study was to reveal the underlying mechanism of psoralen/isopsoralen‐induced hepatotoxicity. Initially, we applied integrated analyses of transcriptomic and metabolomic profiles in mice treated with psoralen and isopsoralen, highlighting the xenobiotic metabolism by cytochromes P450 as a potential pathway. Then, with verifications of expression levels by qRT‐PCR and western blot, affinities by molecular docking, and metabolic contributions by recombinant human CYP450 and mouse liver microsomes, CYP1A2 was screened out as the key metabolic enzyme. Afterwards, CYP1A2 induction and inhibition models in HepG2 cells and mice were established to verify the role of CYP1A2, demonstrating that induction of CYP1A2 aggravated the hepatotoxicity, and conversely inhibition alleviated the hepatotoxic effects. Additionally, we detected glutathione adducts with reactive intermediates of psoralen and isopsoralen generated by CYP1A2 metabolism in biosystems of recombinant human CYP1A2 and mouse liver microsomes, CYP1A2‐overexpressed HepG2 cells, mice livers and the chemical reaction system using UPLC‐Q‐TOF‐MS/MS. Ultimately, the high‐content screening presented the cellular oxidative stress and relevant hepatotoxicity due to glutathione depletion by reactive intermediates. In brief, our findings illustrated that CYP1A2‐mediated metabolic activation is responsible for the psoralen/isopsoralen‐induced hepatotoxicity.

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

Cited by 8 publications

References 37 publications

Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter

Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter

Comparative analysis of the liver‐protective effects of raw and stir‐fried semen of Hovenia dulcis in rats via gas chromatography–mass spectrometry–based serum metabolomic profiling and chemometrics

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen‐induced metabolic activation and hepatotoxicity

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