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 1, * , Hyun-Wook Lee 1, * , Bongkun Choi 1, * , Hsiang-Tsui Wang 1, * , Yu Hu 1 , Manju Mehta 1 , Dhimant Desai 2 , Shantu Amin 2 , Yi Zheng 1 , Moon-Shong Tang 1 1 Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA 2 Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA * These authors have contributed equally to this work Correspondence to: Moon-Shong Tang, email: moon-shong.tang@nyumc.org Keywords: aflatoxin B1, hepatocellular carcinoma, p53 codon 249 mutations, AFB1-8,9-epoxide-deoxyguanosine, cyclic α-methyl-γ-hydroxy-1, N 2 -propano-dG Received: September 22, 2016     Accepted: December 01, 2016     Published: February 14, 2017 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, N 2 -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.