Cytochrome P450 enzymes mediated by DNA methylation is involved in deoxynivalenol-induced hepatoxicity in piglets

Liu, Aimei; Yang, Yunjuan; Guo, Jingchao; Gao, Yan; Wu, Qinghua; Zhao, Liancheng; Sun, Luo; Wang, Xu

doi:10.1016/j.aninu.2021.11.009

Cited by 14 publications

(4 citation statements)

References 61 publications

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“…The emergence of DON in feed is an inevitable and severe problem in the animal husbandry worldwide [ 21 ]. Moreover, DON also severely threatens human health through ecological cycles [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of RIOK2 Functions in Mediating the Toxic Effects of Deoxynivalenol in Porcine Intestinal Epithelial Cells

Gao

Fan

et al. 2022

IJMS

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Deoxynivalenol (DON) is a type of mycotoxin that threatens human and livestock health. Right open reading frame kinase 2 (RIOK2) is a kinase that has a pivotal function in ribosome maturation and cell cycle progression. This study aims to clarify the role of the RIOK2 gene in DON-induced cytotoxicity regulation in porcine intestinal epithelial cells (IPEC-J2). Cell viability assay and flow cytometry showed that the knockdown of RIOK2 inhibited proliferation and induced apoptosis, cell cycle arrest, and oxidative stress in DON-induced IPEC-J2. Then, transcriptome profiling identified candidate genes and pathways that closely interacted with both DON cytotoxicity regulation and RIOK2 expression. Furthermore, RIOK2 interference promoted the activation of the MAPK signaling pathway by increasing the phosphorylation of ERK and JNK. Additionally, we performed the dual-luciferase reporter and ChIP assays to elucidate that the expression of RIOK2 was influenced by the binding of transcription factor Sp1 with the promoter region. Briefly, the reduced expression of the RIOK2 gene exacerbates the cytotoxic effects induced by DON in IPEC-J2. Our findings provide insights into the control strategies for DON contamination by identifying functional genes and effective molecular markers.

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Section: Discussionmentioning

confidence: 99%

Analysis of RIOK2 Functions in Mediating the Toxic Effects of Deoxynivalenol in Porcine Intestinal Epithelial Cells

Gao

Fan

et al. 2022

IJMS

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“…A recent animal study showed that the expressions of CYP2E1 may be related to the DNA methylation of the Cyp2e1 gene (17). In addition, supplementation of S-adenosyl methionine (SAM), a methyl donor for DNA or RNA methylation, was shown to reduce the activity of CYP2E1 and alleviate oxidative liver injury in micropigs fed with a folate-deficient diet plus ethanol (18).…”

Section: Introductionmentioning

confidence: 99%

Folic acid protects against isoniazid-induced liver injury via the m6A RNA methylation of cytochrome P450 2E1 in mice

Jiang,

Ni,

Zhao

et al. 2024

Front. Nutr.

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BackgroundCytochrome P450 2E1 (CYP2E1) converts isoniazid (INH) to toxic metabolites and is critical in INH-induced liver injury. The aim is to investigate the effect of folic acid (FA) on CYP2E1 and INH-induced liver injury.MethodsMale Balb/c mice were used. The mice in the control group only received an AIN-93M diet. The AIN-93M diet was supplemented with 0.66 g INH/kg diet for the mice in the INH and FA groups. The mice in the FA group were treated with additional 0.01 g FA/kg diet. The one-carbon cycle metabolites, the expressions of CYP2E1 and the DNA and RNA methylation levels were detected to reveal the potential mechanism.ResultsFA treatment significantly reduced the alanine aminotransferase level and alleviated the liver necrosis. The mRNA and protein expressions of CYP2E1 were significantly lower in the FA group than those in the INH group. The N6-methyladenosine RNA methylation level of Cyp2e1 significantly increased in the FA group compared with the INH group, while the DNA methylation levels of Cyp2e1 were similar between groups. Additionally, the liver S-adenosyl methionine (SAM)/S-adenosyl homocysteine (SAH) was elevated in the FA group and tended to be positively correlated with the RNA methylation level of Cyp2e1.ConclusionFA alleviated INH-induced liver injury which was potentially attributed to its inhibitory effect on CYP2E1 expressions through enhancing liver SAM/SAH and RNA methylation.

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“…DNA demethylation involves a ten-eleven translocation methylcytosine dioxygenase (TETs) to oxidize 5-methylcytosine (5 mC) into 5-hydroxymethylcytosine (5hmC) ( Kafer et al, 2016 ). DNA methylation affects CYP450 expression ( Liu et al, 2022 ). In a study of lung injury caused by smoking, DNA methylation was found to be the main regulator of CYP450 enzyme expression ( Tekpli et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Nrf2−/− regulated lung DNA demethylation and CYP2E1 DNA methylation under PM2.5 exposure

Jiang

Ding

et al. 2023

Front. Genet.

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Cytochrome P450 (CYP450) can mediate fine particulate matter (PM2.5) exposure leading to lung injury. Nuclear factor E2-related factor 2 (Nrf2) can regulate CYP450 expression; however, the mechanism by which Nrf2−/− (KO) regulates CYP450 expression via methylation of its promoter after PM2.5 exposure remains unclear. Here, Nrf2−/− (KO) mice and wild-type (WT) were placed in a PM2.5 exposure chamber (PM) or a filtered air chamber (FA) for 12 weeks using the real-ambient exposure system. The CYP2E1 expression trends were opposite between the WT and KO mice following PM2.5 exposure. After exposure to PM2.5,CYP2E1 mRNA and protein levels were increased in WT mice but decreased in KO mice, and CYP1A1 expression was increased after exposure to PM2.5 in both WT and KO mice. CYP2S1 expression decreased after exposure to PM2.5 in both the WT and KO groups. We studied the effect of PM2.5 exposure on CYP450 promoter methylation and global methylation levels in WT and KO mice. In WT and KO mice in the PM2.5 exposure chamber, among the methylation sites examined in the CYP2E1 promoter, the CpG2 methylation level showed an opposite trend with CYP2E1 mRNA expression. The same relationship was evident between CpG3 unit methylation in the CYP1A1 promoter and CYP1A1 mRNA expression, and between CpG1 unit methylation in the CYP2S1 promoter and CYP2S1 mRNA expression. This data suggests that methylation of these CpG units regulates the expression of the corresponding gene. After exposure to PM2.5, the expression of the DNA methylation markers ten-eleven translocation 3 (TET3) and 5-hydroxymethylcytosine (5hmC) was decreased in the WT group but significantly increased in the KO group. In summary, the changes in CYP2E1, CYP1A1, and CYP2S1 expression in the PM2.5 exposure chamber of WT and Nrf2−/− mice might be related to the specific methylation patterns in their promoter CpG units. After exposure to PM2.5, Nrf2 might regulate CYP2E1 expression by affecting CpG2 unit methylation and induce DNA demethylation via TET3 expression. Our study revealed the underlying mechanism for Nrf2 to regulate epigenetics after lung exposure to PM2.5.

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Cytochrome P450 enzymes mediated by DNA methylation is involved in deoxynivalenol-induced hepatoxicity in piglets

Cited by 14 publications

References 61 publications

Analysis of RIOK2 Functions in Mediating the Toxic Effects of Deoxynivalenol in Porcine Intestinal Epithelial Cells

Analysis of RIOK2 Functions in Mediating the Toxic Effects of Deoxynivalenol in Porcine Intestinal Epithelial Cells

Folic acid protects against isoniazid-induced liver injury via the m6A RNA methylation of cytochrome P450 2E1 in mice

Nrf2−/− regulated lung DNA demethylation and CYP2E1 DNA methylation under PM2.5 exposure

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