Cellular Responses to Aflatoxin-Associated DNA Adducts [chapter]

Michael Fasullo
2018 Advances in DNA Repair [Working Title]  
Aflatoxin B1 (AFB1) is the most potent known hepatocarcinogen. The signature p53 mutation (p53 249 ser ) that is found in AFB1-associated liver cancer suggests that AFB1 is a potent genotoxin. AFB1 is not genotoxic per se but is metabolically activated by cytochrome P450 enzymes that convert the promutagen into a highly reactive epoxide, which primarily reacts with the N 7 group of guanine, forming 8,9-dihydro-8-(N 7 -guanyl)-9-hydroxyaflatoxin B1 (AFB1-N 7 -dG). While this primary adduct is
more » ... table, the subsequent trans-8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxy aflatoxin B1 (AFB1-Fapy)derived adducts are stable and are mutagenic. Studies have revealed that nucleotide excision repair (NER), base excision repair (BER), recombinational repair, and DNA replication bypass are all involved in conferring AFB1 resistance. To minimize the genotoxicity of AFB1, pathways function to detoxify the metabolically active intermediate, excise resulting DNA adducts, bypass unrepaired adducts, and repair secondary DNA breaks. How these repair pathways functionally cooperate to minimize AFB1-associated genetic instability phenotypes is not well understood. Insights can be gained from epidemiological research and model organisms. Gene profiling and next-generation sequencing are facilitating how pathways and tissuespecific differences are induced. This review will encompass studies concerning human genetic susceptibility to AFB1 and pathways that repair and tolerate AFB1associated DNA damage. ) exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption. European
doi:10.5772/intechopen.81763 fatcat:jmeanai6grgblhz545fkisdgcq