Oncotarget
·
2017
·
IF 5.168
Jie Gao,Gao-Ju Wang,Zhao Wang,Na Gao,Jing Li,Yun-Fei Zhang,Jun Zhou,Hong-Xin Zhang,Qiang Wen,Han Jin,Hai-Ling Qiao
Hepatofibrosis, which leads to cirrhosis and eventual hepatocellular carcinoma, is a common response to chronic toxin-mediated liver injury. Nitrosamines are potent hepatotoxic agents that cause necrosis and subsequent fibrosis in the liver as a result of cytochrome P450 2E1 (CYP2E1)-dependent metabolism, which generates toxic metabolites that form adducts with nucleic acids, leading to hepatotoxicity and mutagenesis. Herein, CYP2E1 activity and content were determined in fibrotic liver tissue from patients with hepatocellular carcinoma. The relationship between CYP2E1 innate activity and hepatofibrogenesis was evaluated, the effect of inhibition of CYP2E1 activity on hepatofibrosis was determined in a Sprague-Dawley rat model of diethylnitrosamine-induced hepatofibrosis. The results demonstrated that the CYP2E1 activities in human fibrotic tissues are significantly higher than that in normal liver tissues. In rats treated with diethylnitrosamine, the livers demonstrated various degree of fibrotic changes and collagen deposition in individual rats. The Ishak score, which determines the stage of fibrosis, correlated with CYP2E1 innate activity, with greater fibrosis in rat livers with higher CYP2E1 innate activity. Inhibition of CYP2E1 during diethylnitrosamine treatment decreased hepatofibrosis and there was an inverse correlation between the degree of inhibition and the extent of hepatofibrosis. Therefore, high CYP2E1 activity is a risk factor for hepatofibrogenesis induced by nitrosamines.
研究领域:
医学
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毒理学
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肝脏研究
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DOI
PubMed
高影响因子
XENOBIOTICA
·
2022
·
IF 1.997
Li Zhang,Fugui Zhang,Yifei Xiao,Jianhao Du,Xingwang Zhang,Min Chen,Baojian Wu
CYP2E1 plays an important role in drug metabolism and drug-induced hepatotoxicity. Here, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in regulation of CYP2E1 expression and acetaminophen (APAP)-induced hepatotoxicity, and to determine the underlying mechanisms.Regulatory effects of REV-ERBα on CYP2E1 expression were assessed in vivo (using Rev-erbα-/- mice) and in vitro (using AML12 and HepG2 cells). In vitro microsomal CYP2E1 activity was probed using its specific substrate p-nitrophenol. Pharmacokinetic and acute toxicity studies were performed with Rev-erbα−/− and wild-type mice after APAP administration.We found that Rev-erbα ablation led to decreases in hepatic CYP2E1 expression and activity in mice. In line with this, APAP-induced hepatotoxicity was attenuated in Rev-erbα-deficient mice. The attenuated toxicity was due to down-regulation of APAP metabolism mediated by CYP2E1, which was evidenced by a decrease in formation of the toxic intermediate metabolite NAPQI (i.e. reduced APAP-cysteine and APAP-N-acetylcysteine levels). Furthermore, positive regulation of CYP2E1 expression by REV-ERBα was confirmed in both AML12 and HepG2 cells. Based on luciferase reporter assays, it was found that REV-ERBα regulated Cyp2e1 transcription and expression through repression of DEC2.In conclusion, REV-ERBα positively regulates CYP2E1 expression in mice, thereby affecting APAP metabolism and hepatotoxicity.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2021
·Vol. 12
·期 1
·1-13
·
IF 8.469
Ge Wenhao,Wang Tao,Zhao Yang,Yang Yunxia,Sun Qi,Yang Xiao,Gao Yan,Xu Xi,Zhang Jianfa
The biological clock is an endogenous biological timing system, which controls metabolic functions in almost all organs. Nutrient metabolism, substrate processing, and detoxification are circadian controlled in livers. However, how the clock genes respond to toxins and influence toxicity keeps unclear. We identified the clock gene Per1 was specifically elevated in mice exposed to toxins such as carbon tetrachloride (CCl 4 ). Mice lacking Per1 slowed down the metabolic rate of toxins including CCl 4 , capsaicin, and acetaminophen, exhibiting relatively more residues in the plasma. Liver injury and fibrosis induced by acute and chronic CCl 4 exposure were markedly alleviated in Per1 -deficient mice. These processes involved the binding of PER1 protein and hepatocyte nuclear factor-1alpha (HNF-1α), which enhances the recruitment of HNF-1α to cytochrome P450 2E1 ( Cyp2e1 ) promoter and increases Cyp2e1 expression, thereby promoting metabolism for toxins in the livers. These results indicate that PER1 mediates the metabolism of toxins and appropriate suppression of Per1 response is a potential therapeutic target for toxin-induced hepatotoxicity.
研究领域:
分子生物学
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药理学
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毒理学
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生物节律学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
·
2018
·Vol. 365
·期 2
·398-407
·
IF 3.706
Jie Gao,Zhao Wang,Gao-Ju Wang,Hong-Xin Zhang,Na Gao,Jie Wang,Cai-E. Wang,Zhao Chang,Yan Fang,Yun-Fei Zhang,Jun Zhou,Han Jin,Hai-Ling Qiao
Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and the third most frequent cause of cancer death worldwide. Diethylnitrosamine (DEN) is one of the recognized risk factors for hepatocarcinogenesis likely due to CYP2E1-mediated metabolic activation. However, CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients has not been determined; the role of CYP2E1 activity, in particular CYP2E1 constitutive activity and CYP2E1 inhibited activity, with respect to the hepatocarcinogenesis induced by DEN is not yet clear. Herein, we determined CYP2E1-mediated DEN metabolic activity in non-neoplastic liver tissue from HCC patients and found that CYP2E1-mediated DEN metabolic activity was significantly elevated with a 43.3% positive rate, and clinicopathologic parameters did not affect the activity. Then, using a Sprague-Dawley rat liver tumor model induced by DEN, the relationship between CYP2E1 constitutive/inhibited activity and hepatocarcinogenesis was explored. The results showed that the CYP2E1 constitutive activity was strongly correlated with tumor incidence and severity of liver tumorigenesis (nodule numbers and size), whereas inhibition of CYP2E1 activity decreased hepatocyte proliferation, liver injury, and liver carcinogenesis in the presence of DEN. In conclusion, the higher CYP2E1 activity would lead to an increased incidence of HCC as a result of CYP2E1-mediated DEN activation. Therefore, higher CYP2E1 activity might be a risk factor for HCC induced by DEN.
研究领域:
肿瘤学
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药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Zixinying Han,Chenxu Liu,Mingrui Li,Mengyan Deng,Ying Ding,Yunchao Li,Meidan Huo,Haiwei Xu,Hailing Qiao,Na Gao
Considerable evidence indicates that CYP2E1 is associated with a variety of inflammatory diseases. Here we evaluated CYP2E1 as a potential therapeutic target for rheumatoid arthritis (RA) and established the protective effect of a new CYP2E1 inhibitor. Gene-expression datasets were used to analyze the change in expression of CYP2E1 in RA patients; CYP2E1 activity in collagen-induced arthritis (CIA) rats was determined by HPLC. We further evaluated the protective effects of C yp2e1 knockout and a CYP2E1-specific inhibitor, Q11, synthesized by our group, in CIA and adjuvant-induced arthritis (AIA) rats. The expression of CYP2E1 in synovial tissue was elevated in RA patients and in CIA rats and the activity of CYP2E1 in vivo and in vitro in CIA rats was greater than that of controls. C yp2e1 knockout significantly reduced the incidence of CIA and alleviated the severity of symptoms. Treatment with different doses of Q11 decreased paw thickness, volume and arthritis scores and reduced the serum levels of IL‐6, TNF‐α, IL‐1β and MDA, and increased the level of GSH in CIA rats. A similar inhibitory effect was exhibited for Q11 in the AIA rats. Moreover, Q11 significantly impeded proliferation, migration, and invasion of human rheumatoid arthritis synovial fibroblasts cells. Q11 decreased the release of ROS and enhanced Nrf2 nuclear translocation and HO-1 expression in the cell nucleus. Overall, our results indicated that CYP2E1 may be a new target for RA and Q11 has potential protective effects against RA by reducing oxidative stress and opposing the inflammatory response via the ROS/Nrf2/HO-1 signaling pathway.
研究领域:
药理学
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免疫学
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风湿病学
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DOI
PubMed
高影响因子
Revista Brasileira de Farmacognosia-Brazilian Journal of Pharmacognosy
·
2023
·Vol. 33
·期 5
·1060-1071
·
IF 1.6
Zhang Yan,Lu Qian,Liu Shasha,Chai Yuanyuan,Dai Mingxin,Deng Zhongkang,Huang Xin,Zhang Luyong,Yu Qinwei,Jiang Zhenzhou
Excessive administration of the antipyretic and analgesic drug acetaminophen can cause acute liver injury. The mechanism is that a large amount of N -acetyl- p -benzoquinone-imine is generated through the metabolism of cytochrome P450 (CYP450), which leads to cell necrosis, oxidative stress, and inflammation. The purpose of this study was to investigate the protective effect of psoralen on acetaminophen-induced acute liver injury, and to clarify the isoform CYP2E1 of human cytochrome P450 in the efficacy of it. The results showed that psoralen ameliorated hepatocyte necrosis by decreasing serum aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, oxidative stress index malondialdehyde and inflammatory cytokines, such as interleukins (Il6 and Il1β) and tumor necrosis factor (Tnfα) in mice. Molecular docking suggested that psoralen could bind to active sites of CYP2E1, CYP1A2 and CYP3A11. A single dose of psoralen could significantly inhibit the enzymatic activity of CYP2E1 in rats, while administration of psoralen for 5 days had no significant effect on CYP2E1. In conclusion, psoralen can ameliorate acetaminophen-induced acute liver injury, specifically by reducing hepatocyte necrosis, inflammation and oxidative stress. Psoralen could be the substrate of CYP2E1 which can competitively bind to its active site, thereby competing with acetaminophen, thus inhibiting the enzymatic activity of CYP2E1 to have an impact on rates of drug metabolism in the liver. Graphical Abstract
研究领域:
药理学
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肝病学
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毒理学
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DOI
高影响因子
MOLECULAR CARCINOGENESIS
·
2019
·Vol. 58
·期 8
·1481-1491
·
IF 3.411
Yuan-yuan Guo,Chen Xu,Yan Fang,Cai-e Wang,Na Gao,Qiang Wen,Hai-ling Qiao
Cytochrome P450 2E1 (CYP2E1) is an important drug-metabolizing enzyme that has been recognized as one of the risk factors for hepatofibrosis. Macrophages play key roles in regulating hepatofibrosis progression and resolution. However, whether CYP2E1 is involved in the regulation of macrophage polarization during hepatofibrosis is still unclear. Herein, we measured CYP2E1 activity and the expression of CD163 (an M2 marker) and CD68 (a pan-macrophage marker) in hepatofibrotic tissue from HCC patients (n = 26) with comparison to normal liver tissue (n = 26). The relationship of CYP2E1 activity in vivo and the CD163/CD68 ratio (an indicator of M2 polarization), as well as the extent of hepatofibrosis, were evaluated in diethylnitrosamine (DEN)-treated Sprague-Dawley rats. Strikingly, CYP2E1 activity and expression of CD68 increased and the CD163/CD68 ratio decreased, especially in hepatofibrotic tissue with higher CYP2E1 activity. Expression of α-SMA, Ki67, and PCNA were positively correlated with CYP2E1 activity and inversely correlated with the CD163/CD68 ratio. Furthermore, CYP2E1 activity showed an inverse correlation with the CD163/CD68 ratio. Overall, high CYP2E1 activity aggravates hepatofibrosis by restraining M2 macrophage polarization, providing a novel insight for understanding the profibrotic activity of CYP2E1 and a promising avenue for hepatofibrosis therapy.
研究领域:
肝病学
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免疫学
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药理学
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DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
·
2021
·
IF 2.903
Hai-Yan Jiang,Yan-Ni Bao,Feng-Mei Lin,Yong Jin
Triptolide (TP), the main active compound extracted from medicine- tripterygium wilfordii Hook f. (TWHF). It has anti-tumor and immunomodulatory properties. Our study aimed to investigate the mechanisms of hepatotoxicity treated with TP in vivo and in vitro, as well as their relationship with the NF-κB (p65) signal pathway; and to assess TP-induced hepatotoxicity after CYP2E1 modulation by the known inhibitor, clomethiazole, and the known inducer, pyrazole. Mice were given TP to cause liver injury and IHHA-1 cells were given TP to cause hepatocyte injury. The enzyme activity and hepatotoxicity changed dramatically when the CYP2E1 inhibitor and inducer were added. In comparison to the control group, the enzyme inducer increased the activity of CYP2E1, whereas the enzyme inhibitor had the opposite effect. Our findings suggest that TP is an inducer of CYP2E1 via a time-dependent activation mechanism. In addition, TP can promote oxidative stress, inflammatory and involving the NF-κB (p65) signal pathway. Therefore, we used triptolide to stimulate C57 mice and IHHA-1 cells to determine whether TP can promote oxidative stress and inflammation by activating CYP2E1 in response to exacerbated liver damage and participate in NF-κB (p65) signaling pathway.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Weiqi Cui,Qianwen Cao,Luyao Liu,Xuecui Yin,Xiaohan Wang,Yang Zhao,Yanhong Wang,Bo Wei,Xia Xu,Youcai Tang
Background The hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP. Methods In this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection. Results Compared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC–MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels. Conclusion AAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway.
研究领域:
药理学
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肝病学
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毒理学
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代谢组学
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中药学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2023
·
IF 3.9
Shasha Liu,Ruohan Cheng,Hui He,Kunming Ding,Rongmi Zhang,Yuanyuan Chai,Qinwei Yu,Xin Huang,Luyong Zhang,Zhenzhou Jiang
This study aimed to investigate the effect and mechanism of 8-methoxypsoralen (8-MOP) on acetaminophen (APAP)-induced hepatotoxicity in mice. The study found that 1 h after intraperitoneal injection of 300 mg/kg APAP, treatment with 40 mg/kg, 80 mg/kg and 120 mg/kg 8-MOP could reduce serum transaminase level and histopathological liver necrosis area. Elevated mRNA expression of liver inflammatory mediators caused by excessive APAP was also reversed. 8-MOP significantly reduced APAP-induced hepatotoxicity dose-dependently, and the highest therapeutic dose of 8-MOP (120 mg/kg) had no harmful effects on the liver. Cocktail probe assay revealed that 8-MOP can inhibit Cyp2e1 enzymatic activities of mice, thereby reducing the production of acetaminophen-cysteine (APAP-CYS), a toxic metabolite of APAP. 8-MOP had no significant effect on the protein and gene expression of Cyp2e1. The three-dimensional structures of mouse Cyp2e1 were constructed by homologous modeling. Molecular docking showed that 8-MOP had a good binding effect on the enzyme activity site of Cyp2e1. In summary, 8-MOP dose-dependently attenuated APAP-induced hepatotoxicity by binding to Cyp2e1 and occupying the active center of the enzyme, thus competitively inhibiting the oxidative metabolism of APAP, and reducing the generation of toxic product APAP-CYS.
研究领域:
药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Analytical Methods
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2025
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IF 2.6
Hua Sun,Ming Li,Jin-Ling Song,Chun-Zhi Ai,Wei Li
Developing a convenient, accurate, and cost-effective analytical method for the detection of Cytochrome P450 (CYP) mediated drug bioactivation remains a challenge. The present study proposes a method using Raman spectroscopy (RS) combined with machine learning algorithms to classify CYP2E1-expressing cells that were subjected to acetaminophen (APAP) metabolic activation. Raman spectra obtained from the cells were subjected to dimensionality reduction using principal component analysis (PCA), and machine learning algorithms were employed for further classification. Four models, i.e., PCA-k-nearest neighbors (KNN), PCA-support vector machine (SVM), PCA-logistic regression (LR) and PCA-random forest (RF), were established and effectively classified APAP-treated cells with or without CYP2E1 expression. The PCA-SVM model exhibited the highest accuracy, with a value of 94.49%. Feature analysis revealed that signals at 1440, 999, 645, 618, 1089, 1340, 1655, 1319, 716, 1123, 847, 745, 823, and 956 cm−1 were the key features that were responsible for the classification, which indicated alterations in lipids, nucleic acids, and amino acids in the cells. This study established the feasibility of combining RS and machine learning for the detection of CYP2E1 activity, offering a promising platform for rapid drug metabolism studies.
研究领域:
分析化学
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药理学
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生物医学工程
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光谱学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
Biomedicines
·
2024
·Vol. 12
·期 7
·1505
·
IF 3.9
Qi Zhang,Shuang Wu,Qiubing Chen,Yahong Zhang,Cai Zhang,Runting Yin,Zhen Ouyang,Yuan Wei
The prevalence of excessive drinking-related alcoholic liver disease (ALD) is rising, yet therapeutic options remain limited. High alcohol consumption and consequent oxidative metabolism by cytochrome P450 (CYP) can lead to extremely high levels of reactive oxygen species, which overwhelm cellular defenses and harm hepatocytes. Our previous investigations showed that inhibitingCyp2e1using RNA interference reduced the incidence of ALD. However, compensatory mechanisms other than CYP2E1 contribute to oxidative stress in the liver. Therefore, we coupled triple siRNA lipid nanoparticles (LNPs) targetingCyp2e1with two isoenzymesCyp4a10andCyp4a14to treat ALD mouse models fed with Lieber–Decarli ethanol liquid diet for 12 weeks at the early (1st week), middle (5th week), and late (9th week) stages. The administration of triple siRNA LNPs significantly ameliorated chronic alcoholic liver injury in mice, and early treatment achieved the most profound effects. These effects can be attributed to a reduction in oxidative stress and increased expression of antioxidant genes, includingGsh-Px,Gsh-Rd, andSod1. Moreover, we observed the alleviation of inflammation, evidenced by the downregulation ofIl-1β,Il-6,Tnf-α, andTgf-β, and the prevention of excessive lipid synthesis, evidenced by the restoration of the expression ofSrebp1c,Acc, andFas. Finally, triple siRNA treatment maintained normal metabolism in lipid oxidation. In brief, our research examined the possible targets for clinical intervention in ALD by examining the therapeutic effects of triple siRNA LNPs targetingCyp2e1,Cyp4a10, andCyp4a14. The in vivo knockdown of the three genes in this study is suggested as a promising siRNA therapeutic approach for ALD.
研究领域:
肝病学
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分子生物学
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药理学
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治疗学
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产品关联
DOI
PubMed
高影响因子
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