AFG₁-induced TNF-α-mediated inflammation enhances gastric epithelial cell injury via CYP2E1

Aflatoxin G₁ (AFG₁), a member of the aflatoxin family with cytotoxic and carcinogenic properties, is one of the most common mycotoxins occurring in various agricultural products, animal feed, and human foods and drinks worldwide. Epithelial cells in the gastrointestinal tract are the first line of defense against ingested mycotoxins. However, the toxicity of AFG₁ to gastric epithelial cells (GECs) remains unclear. In this study, we explored whether and how AFG₁-induced gastric inflammation regulates cytochrome P450 to contribute to DNA damage in GECs. Oral administration of AFG₁ induced gastric inflammation and DNA damage in mouse GECs associated with P450 2E1 (CYP2E1) upregulation. Treatment with the soluble TNF-α receptor sTNFR:Fc inhibited AFG₁-induced gastric inflammation, and reversed CYP2E1 upregulation and DNA damage in mouse GECs. TNF-α-mediated inflammation plays an important role in AFG₁-induced gastric cell damage. Using the human gastric cell line GES-1, AFG₁ upregulated CYP2E1 through NF-κB, causing oxidative DNA damage in vitro. The cells were also treated with TNF-α and AFG₁ to mimic AFG₁-induced TNF-α-mediated inflammation. TNF-α activated the NF-κB/CYP2E1 pathway to promote AFG₁ activation, which enhanced DNA cellular damage in vitro. In conclusion, AFG₁ ingestion induces TNF-α-mediated gastric inflammation, which upregulates CYP2E1 to promote AFG₁-induced DNA damage in GECs.