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.
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.
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Mao-Wen
authors.initials: MW
authors.lastname: Weng
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Bongkun
authors.initials: B
authors.lastname: Choi
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Hsiang-Tsui
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Manju
authors.initials: M
authors.lastname: Mehta
authors.affiliation: Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Shantu
authors.initials: S
authors.lastname: Amin
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Moon-Shong
authors.initials: MS
authors.lastname: Tang
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D000447:Aldehydes / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003062:Codon / Q000187:drug effects; D018736:DNA Adducts / Q000096:biosynthesis*; D004260:DNA Repair / Q000187:drug effects*; D016158:Genes, p53 / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation
chemical_list: D000447:Aldehydes; D003062:Codon; D018736:DNA Adducts; D016604:Aflatoxin B1
keywords: AFB1-8,9-epoxide-deoxyguanosine; aflatoxin B1; cyclic α-methyl-γ-hydroxy-1,N2-propano-dG; hepatocellular carcinoma; p53 codon 249 mutations