Psoralen induces liver injuries through endoplasmic reticulum stress signaling in female mice

Yu, Ruili; Yu, Yingli; Su, Shijia; Zhao, Lin; Wang, Qin; Zhang, Yue; Song, Lei; Zhou, Kun

doi:10.1080/01480545.2021.1881537

Cited by 7 publications

(8 citation statements)

References 26 publications

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“…In a study, mice’s liver coefficients significantly increased after receiving psoralen continuously for three days at a dose of 80 mg/kg, and the liver developed inflammatory cell foci and vacuolar degeneration. Additionally, the endoplasmic reticulum stress-related markers Grp78, PERK, eif2, ATF4, ire1, ATF6 and XBP1 expression and transcription levels significantly increased [ 147 ]. These findings suggested that psoralen could induce endoplasmic reticulum stress to cause liver damage.…”

Section: Hepatotoxicitymentioning

confidence: 99%

“…Over 163 chemicals have so far been identified from fresh PCL. A number of phytochemical studies have revealed that PCL primarily contains coumarins , flavonoids , monoterpene phenols , benzofurans (140)(141)(142)(143)(144)(145)(146)(147)(148)(149) and other compounds (150)(151)(152)(153)(154)(155)(156)(157)(158)(159)(160)(161)(162)(163). Among them, coumarins, flavonoids and monoterpene phenols are considered to be the PCL's primary bioactive components.…”

Section: Phytochemistrymentioning

confidence: 99%

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Psoralea corylifolia L.: a comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics

Chen

Sun

et al. 2023

Chin Med

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Psoralea corylifolia L. (PCL), referred to as “Bu-gu-zhi” in Chinese, has great medicinal values since ancient times. PCL is the dried ripe fruit of Psoralea corylifolia L., which has been widely used in traditional Chinese medicine (TCM) for the treatment of kidney-yang deficiency, enuresis and urinary frequency, chills and pain of the waist and knees, dawn diarrhea and vitiligo. In this paper, a systematic of the botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics of PCL was presented, along with future research directions. According to the results, PCL contains approximately 163 chemical components, including coumarins, flavonoids, monoterpene phenols, benzofurans, glycosides, lipids, fatty acids, and volatile oils. PCL and its active ingredients have a variety of pharmacological activities, such as anti-inflammatory, antibacterial, antiviral, antioxidant, antitumor, antiosteoporosis, cardioprotective, neuroprotective, and immunomodulatory. Further study of quality control standards and potential mechanisms of PCL is also needed. In addition, more toxicological studies will also contribute to the progress of clinical trials.

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Section: Hepatotoxicitymentioning

confidence: 99%

Section: Phytochemistrymentioning

confidence: 99%

Psoralea corylifolia L.: a comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics

Chen

Sun

et al. 2023

Chin Med

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“…Psoralen and isopsoralen are not only present in PF, but also widely occurring in other Psoralea medicinal plants (Koul, Taak, Kumar, Kumar, & Sanyal, 2019). The hepatotoxicities of these two constituents have been frequently reported (Wang et al, 2019;Yang et al, 2020;Yu et al, 2021;Zhang et al, 2019;Zhou et al, 2018), so it is vital to clarify the hepatotoxic mechanism for the clinical According to previous studies, many constituents in PF interacted with various CYP450 enzymes, viz. certain components affected the expression of CYP450, and simultaneously their metabolisms were regulated by CYP450 (Shi et al, 2020;Zhou et al, 2019), but it remained unclear that the main CYP450 isoform responsible for psoor isopsoralen metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Psoralen and isopsoralen are not only present in PF , but also widely occurring in other Psoralea medicinal plants (Koul, Taak, Kumar, Kumar, & Sanyal, 2019). The hepatotoxicities of these two constituents have been frequently reported (Wang et al, 2019; Yang et al, 2020; Yu et al, 2021; Zhang et al, 2019; Zhou et al, 2018), so it is vital to clarify the hepatotoxic mechanism for the clinical application of Psoralea herbs. This study revealed that psoralen/isopsoralen‐induced hepatotoxicity in vitro or in vivo was mainly through the metabolic activation of CYP1A2 to form reactive intermediates, deplete GSH, and consequently stimulate cellular oxidative stress.…”

Section: Discussionmentioning

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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“…Oxymatrine in Sophora flavescens can also induce the occurrence of ERS and the phosphorylation of c-JNK through the excessive accumulation of reactive oxygen species, causing LO2 apoptosis, which can be alleviated by 4-PBA [ 94 ]. In vivo studies found that psoralen induces ERS in hepatocytes of female C57 mice, increases liver injury-related factors’ expression, and causes inflammatory infiltration and vacuolar degeneration in hepatocytes [ 95 ]. The mechanism of DILI is indeed very complex, involving various mechanisms such as protein dysfunction, inflammation, oxidative stress, mitochondrial damage, and autoimmune response.…”

Section: The Important Role Of Endoplasmic Reticulum Stress In Liver ...mentioning

confidence: 99%

Endoplasmic reticulum stress-mediated cell death in liver injury

et al. 2022

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The endoplasmic reticulum is an important intracellular organelle that plays an important role in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are induced when the body is exposed to adverse external stimuli. It has been established that ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, and pyroptosis, through three major transmembrane receptors on the ER membrane, including inositol requirement enzyme 1α, protein kinase-like endoplasmic reticulum kinase and activating transcription factor 6. These different modes of cell death play an important role in the occurrence and development of various diseases, such as neurodegenerative diseases, inflammation, metabolic diseases, and liver injury. As the largest metabolic organ, the liver is rich in enzymes, carries out different functions such as metabolism and secretion, and is the body’s main site of protein synthesis. Accordingly, a well-developed endoplasmic reticulum system is present in hepatocytes to help the liver perform its physiological functions. Current evidence suggests that ERS is closely related to different stages of liver injury, and the death of hepatocytes caused by ERS may be key in liver injury. In addition, an increasing body of evidence suggests that modulating ERS has great potential for treating the liver injury. This article provided a comprehensive overview of the relationship between ERS and four types of cell death. Moreover, we discussed the mechanism of ERS and UPR in different liver injuries and their potential therapeutic strategies.

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Psoralen induces liver injuries through endoplasmic reticulum stress signaling in female mice

Cited by 7 publications

References 26 publications

Psoralea corylifolia L.: a comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics

Psoralea corylifolia L.: a comprehensive review of its botany, traditional uses, phytochemistry, pharmacology, toxicology, quality control and pharmacokinetics

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

Endoplasmic reticulum stress-mediated cell death in liver injury

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