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

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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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-epoxidedeoxyguanosine (AFB1-E-dG) induced by AFB1-E and cyclic a-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-OHPdG 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-OHPdG formation and repair shape the codon 249 mutational hotspot.

Original languageEnglish (US)
Pages (from-to)18213-18226
Number of pages14
JournalOncotarget
Volume8
Issue number11
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology

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