Human CYP1B1 enzyme-mediated, AhR enhanced activation of aflatoxin B1 for its genotoxicity in human cells

Chen, Yuting; Lu, Zhaohong; Li, Boxin; Wang, Huanhuan; Jiang, Tikeng; Xuan, Mei; Yang, Hua; Chen, Jialong; Liu, Xiaoshan; Liang, Hairong; Liu, Yungang; Tang, Huanwen

doi:10.1016/j.toxlet.2022.11.014

Cited by 6 publications

(1 citation statement)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Arachidonic acid can be converted to various metabolites through the cytochrome P450 enzyme system [ 20 ]. Cytochrome P450 family members are crucial early responsive genes that catalyze the metabolism of mycotoxins [ 21 ]. CYP450 activation is thought to be a significant signal for the metabolic activation of toxic or carcinogenic metabolites [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolomics and Transcriptomics Analyses of Curcumin Alleviation of Ochratoxin A-Induced Hepatotoxicity

Hui,

Zheng,

Dong

et al. 2023

IJMS

View full text Add to dashboard Cite

Ochratoxin A (OTA) is one of the mycotoxins that poses a serious threat to human and animal health. Curcumin (CUR) is a major bioactive component of turmeric that provides multiple health benefits. CUR can reduce the toxicities induced by mycotoxins, but the underlying molecular mechanisms remain largely unknown. To explore the effects of CUR on OTA toxicity and identify the key regulators and metabolites involved in the biological processes, we performed metabolomic and transcriptomic analyses of livers from OTA-exposed mice. We found that CUR can alleviate the toxic effects of OTA on body growth and liver functions. In addition, CUR supplementation significantly affects the expressions of 1584 genes and 97 metabolites. Integrated analyses of transcriptomic and metabolomic data showed that the pathways including Arachidonic acid metabolism, Purine metabolism, and Cholesterol metabolism were significantly enriched. Pantothenic acid (PA) was identified as a key metabolite, the exogenous supplementation of which was observed to significantly alleviate the OTA-induced accumulation of reactive oxygen species and cell apoptosis. Further mechanistical analyses revealed that PA can downregulate the expression level of proapoptotic protein BAX, enhance the expression level of apoptosis inhibitory protein BCL2, and decrease the level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). This study demonstrated that CUR can alleviate the adverse effects of OTA by influencing the transcriptomic and metabolomic profiles of livers, which may contribute to the application of CUR in food and feed products for the prevention of OTA toxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolomics and Transcriptomics Analyses of Curcumin Alleviation of Ochratoxin A-Induced Hepatotoxicity

Hui,

Zheng,

Dong

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

Bergapten Ameliorates Psoriatic Skin Lesions and IL‐17A‐Induced Activation of the NF‐κB Signaling Pathway via the Downregulation of CYP1B1

Zhu,

Cheng,

Chen

et al. 2024

Phytotherapy Research

View full text Add to dashboard Cite

Bergapten (BP) is a plant‐derived furocoumarin that has a wide range of pharmacological effects. BP serves as a candidate amplifier in phototherapy against skin inflammation, such as psoriasis and atopic dermatitis. However, the anti‐inflammatory role of BP remains elusive. We utilized IL‐17A‐stimulated keratinocyte line and imiquimod‐challenged BALB/c mice to imitate psoriasis‐like inflammation. Inflammatory phenotypes were determined by expressions of inflammatory genes and cytokines, histopathological changes and activities of nuclear factor‐κB (NF‐κB) pathway. An RNA‐seq analysis of rodent skin was performed to explore possible mechanism lying behind. SiRNAs and antagonist (TMS) against cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were subsequently used to determine the role of CYP1B1 in psoriasis pathogenesis in vitro and in vivo. Overexpression of CYP1B1 with lentivirus further validate therapeutic effect of BP. BP significantly suppressed activation of the NF‐κB pathway by inhibiting p65 phosphorylation and improved the inflammatory phenotype both in vitro and in vivo. We revealed the key role of CYP1B1 in regulating the activation of the NF‐κB signaling pathway. Knock‐down with siRNAs significantly reduce the expression of inflammatory genes and cytokines. An intraperitoneal injection of TMS partially remediated IMQ‐induced inflammation, mainly in terms of skin thickness. Overexpression of Cyp1b1 led to increased expression of the CYP1B1 protein and rescued the therapeutic effect of BP in vitro. This study revealed that BP suppressed expression of Cyp1b1 in keratinocytes and inhibited the activation of NF‐κB signaling pathway by blocking the phosphorylation of p65.

show abstract

New insights into aflatoxin B1 mechanistic toxicology in cattle liver: an integrated approach using molecular docking and biological evaluation in CYP1A1 and CYP3A74 knockout BFH12 cell lines

Iori,

Lahtela-Kakkonen,

D’Onofrio

et al. 2024

Arch Toxicol

View full text Add to dashboard Cite

Aflatoxin B1 (AFB1) is a pro-carcinogenic compound bioactivated in the liver by cytochromes P450 (CYPs). In mammals, CYP1A and CYP3A are responsible for AFB1 metabolism, with the formation of the genotoxic carcinogens AFB1-8,9-epoxide and AFM1, and the detoxified metabolite AFQ1. Due to climate change, AFB1 cereals contamination arose in Europe. Thus, cattle, as other farm animals fed with grains (pig, sheep and broiler), are more likely exposed to AFB1 via feed with consequent release of AFM1 in milk, posing a great concern to human health. However, knowledge about bovine CYPs involved in AFB1 metabolism is still scanty. Therefore, CYP1A1- and CYP3A74-mediated molecular mechanisms of AFB1 hepatotoxicity were here dissected. Molecular docking of AFB1 into CYP1A1 model suggested AFB1 8,9-endo- and 8,9-exo-epoxide, and AFM1 formation, while docking of AFB1 into CYP3A74 pointed to AFB1 8,9-exo-epoxide and AFQ1 synthesis. To biologically confirm these predictions, CYP1A1 and CYP3A74 knockout (KO) BFH12 cell lines were exposed to AFB1. LC–MS/MS investigations showed the abolished production of AFM1 in CYP1A1 KO cells and the strong increase of parent AFB1 in CYP3A74 KO cells; the latter result, coupled to a decreased cytotoxicity, suggested the major role of CYP3A74 in AFB1 8,9-exo-epoxide formation. Finally, RNA-sequencing analysis indirectly proved lower AFB1-induced cytotoxic effects in engineered cells versus naïve ones. Overall, this study broadens the knowledge on AFB1 metabolism and hepatotoxicity in cattle, and it provides the weight of evidence that CYP1A1 and CYP3A74 inhibition might be exploited to reduce AFM1 and AFBO synthesis, AFB1 toxicity, and AFM1 milk excretion.

show abstract

Human CYP1B1 enzyme-mediated, AhR enhanced activation of aflatoxin B1 for its genotoxicity in human cells

Cited by 6 publications

References 34 publications

Metabolomics and Transcriptomics Analyses of Curcumin Alleviation of Ochratoxin A-Induced Hepatotoxicity

Metabolomics and Transcriptomics Analyses of Curcumin Alleviation of Ochratoxin A-Induced Hepatotoxicity

Bergapten Ameliorates Psoriatic Skin Lesions and IL‐17A‐Induced Activation of the NF‐κB Signaling Pathway via the Downregulation of CYP1B1

New insights into aflatoxin B1 mechanistic toxicology in cattle liver: an integrated approach using molecular docking and biological evaluation in CYP1A1 and CYP3A74 knockout BFH12 cell lines

Contact Info

Product

Resources

About