Cellular Responses to Aflatoxin-Associated DNA Adducts

Abstract

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 unstable, 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.

Whole exome and transcript profiling of liver following aflatoxin B1 exposure in rats

“…Rats closely mimic human AFB1 metabolite‐induced DNA adduct formation, glutathione‐based detoxification mechanisms, and develop hepatocellular carcinomas secondary to aberrations in NER. Mice, on the other hand, have inherent limitations when compared with human AFB1 metabolism and liver detoxification (Fasullo, 2018; Taguchi et al, 2016; Wild & Turner, 2002). NER is quite effective in mice secondary to AFB1 exposure.…”

The Effect of Aflatoxin B1 on Tumor-Related Genes and Phenotypic Characters of MCF7 and MCF10A Cells

“…Once inside the cell, the stable form of AB1 is metabolized by the enzyme cytochrome P450, resulting in the production of highly unstable aflatoxin-8, 9-epoxide. In this unstable form, the toxin binds to DNA molecules to gain stability at high affinity causing the formation of aflatoxin-N7-guanine [ 11 ]. At this point, a transversion mutation takes place where a guanine (G) base will be transversed to a thymine (T) base [ 12 ].…”