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Publication Detail

Title: AFB1 hepatocarcinogenesis is via lipid peroxidation that inhibits DNA repair, sensitizes mutation susceptibility and induces aldehyde-DNA adducts at p53 mutational hotspot codon 249.

Authors: Weng, Mao-Wen; Lee, Hyun-Wook; Choi, Bongkun; Wang, Hsiang-Tsui; Hu, Yu; Mehta, Manju; Desai, Dhimant; Amin, Shantu; Zheng, Yi; Tang, Moon-Shong

Published In Oncotarget, (2017 Mar 14)

Abstract: Aflatoxin B1 (AFB1) contamination in the food chain is a major cause of hepatocellular carcinoma (HCC). More than 60% of AFB1 related HCC carry p53 codon 249 mutations but the causal mechanism remains unclear. We found that 1) AFB1 induces two types of DNA adducts in human hepatocytes, AFB1-8,9-epoxide-deoxyguanosine (AFB1-E-dG) induced by AFB1-E and cyclic α-methyl-γ-hydroxy-1,N2-propano-dG (meth-OH-PdG) induced by lipid peroxidation generated acetaldehyde (Acet) and crotonaldehyde (Cro); 2) the level of meth-OH-PdG is >30 fold higher than the level of AFB1-E-dG; 3) AFB1, Acet, and Cro, but not AFB1-E, preferentially induce DNA damage at codon 249; 4) methylation at -CpG- sites enhances meth-OH-PdG formation at codon 249; and 5) repair of meth-OH-PdG at codon 249 is poor. AFB1, Acet, and Cro can also inhibit DNA repair and enhance hepatocyte mutational sensitivity. We propose that AFB1-induced lipid peroxidation generated aldehydes contribute greatly to hepatocarcinogenesis and that sequence specificity of meth-OH-PdG formation and repair shape the codon 249 mutational hotspot.

PubMed ID: 28212554 Exiting the NIEHS site

MeSH Terms: Aflatoxin B1/toxicity*; Aldehydes/metabolism*; Carcinoma, Hepatocellular/chemically induced; Carcinoma, Hepatocellular/genetics; Carcinoma, Hepatocellular/metabolism; Carcinoma, Hepatocellular/pathology; Codon/drug effects; DNA Adducts/biosynthesis*; DNA Repair/drug effects*; Genes, p53/drug effects*; Hep G2 Cells; Humans; Lipid Peroxidation/drug effects; Liver Neoplasms/chemically induced*; Liver Neoplasms/genetics; Liver Neoplasms/metabolism; Liver Neoplasms/pathology; Mutation

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