CYP2E1 and miRNA‐378a‐3p contribute to acetaminophen‐ or tripterygium glycosides‐induced hepatotoxicity

Chen, Keguang; Guo, Nan; Zhang, Rui; Wei, Chen; Guo, Ruru

doi:10.1111/bcpt.13313

Cited by 12 publications

(3 citation statements)

References 44 publications

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“…As CYP2E1 is the major source of NAPQI, an evaluation of the CYP2E1 expression level was done in this study. APAP treatment caused a significant increase in CYP2E1 mRNA level compared to the control group and this finding was in accordance with the reported results that CYP2E1 could play a major role in APAP-induced cytotoxicity ( Knockaert et al, 2011 ; Chen et al, 2020 ). Administration of PA in APAP-induced hepatotoxicity in this study produced a significant reduction in the CYP2E1 mRNA level.…”

Section: Discussionsupporting

confidence: 92%

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice

Hassan,

Abdel-Halim,

El-Shenbaby

et al. 2024

Front. Pharmacol.

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Introduction: Administration of high doses of acetaminophen (APAP) results in liver injury. Oxidative stress and iron overload play roles in the pathogenesis of APAP-induced hepatotoxicity. The present study assessed the potential hepatoprotective effects of phytic acid (PA), a natural antioxidant and iron chelator, on APAP-induced hepatotoxicity and the possible underlying mechanism through its effects on CYP2E1 gene expression, iron homeostasis, oxidative stress, and SIRT-1 expression levels.Methods: Twenty-four adult male albino mice were used in this study. Mice were divided into four groups (six mice in each group): control, APAP-treated, PA-treated and APAP + PA-treated groups. Liver function tests, serum and liver tissue iron load were evaluated in all the study groups. Hepatic tissue homogenates were used to detect oxidative stress markers, including malondialdehyde (MDA) and reduced glutathione (GSH). Histological hepatic evaluation and immunohistochemistry of SIRT-1 were performed. Quantitative real-time PCR was used for the assessment of CYP2E1 and SIRT-1 gene expressions. APAP-induced biochemical and structural hepatic changes were reported.Results: PA administration showed beneficial effects on APAP-induced hepatotoxicity through improvements in liver functions, decreased CYP2E1 gene expression, decreased serum and liver iron load, decreased MDA, increased GSH, increased SIRT-1 expression level and improvement in hepatic architecture.Conclusion: Conclusively, PA can be considered a potential compound that can attenuate acetaminophen-induced hepatotoxicity through its role as an iron chelator and antioxidant, as well as the up-regulation of SIRT-1 and down-regulation of CYP2E1.

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Section: Discussionsupporting

confidence: 92%

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice

Hassan,

Abdel-Halim,

El-Shenbaby

et al. 2024

Front. Pharmacol.

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“…Another transcription factor, Pregnane X Receptor (PXR), also induces metabolizing enzymes such as CYP3A4. The levels of PXR are found to be low during miR-148a overexpression(refer to Table 3) 57,58 .…”

Section: Mirnas Regulating Cytochromesmentioning

confidence: 99%

Genetic and Epigenetic Basis of Drug-Induced Liver Injury

et al. 2023

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Drug induced liver injury (DILI) is a rare but severe adverse drug reaction seen in pharmacotherapy and a major cause of post-marketing drug withdrawals. Advances in genome-wide studies indicate that genetic and epigenetic diversity can lead to inter-individual differences in drug response and toxicity. It is necessary to identify how the genetic variations, in the presence of environmental factors can contribute to development and progression of DILI. Studies on microRNA, histone modification and DNA methylation, SNPs related to DILI were retrieved from databases and were analyzed for the current research and updates develop this narrative review. We have compiled some of the major genetic, epigenetic, pharmacogenetic factors leading to DILI. Many validated genetic risk factors of DILI, such as variants of drug-metabolising enzymes, HLA alleles and some transporters were identified. In conclusion, these studies provide useful information in risk alleles identification and implementing personalised medicine.

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“…7,8 At the same time, CYP2E1 expression level may increase both trypterygium glycosides and TP. 9 Therefore, it is important to understand the toxicity of the TP mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Triptolide regulates oxidative stress and inflammation leading to hepatotoxicity via inducing CYP2E1

et al. 2021

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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.

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CYP2E1 and miRNA‐378a‐3p contribute to acetaminophen‐ or tripterygium glycosides‐induced hepatotoxicity

Cited by 12 publications

References 44 publications

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice

Genetic and Epigenetic Basis of Drug-Induced Liver Injury

Triptolide regulates oxidative stress and inflammation leading to hepatotoxicity via inducing CYP2E1

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