Molecular and cellular events associated with aflatoxin-induced hepatocarcinogenesis

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Abstract
Aflatoxin B1 (AFB1) is a potent carcinogen for the liver of many experimental animals, and has recently been classified as a human carcinogen on the basis of experimental data and epidemiologic studies in exposed human populations. Covalent binding to DNA resulting from metabolic activation to the 9, 10 oxide is considered to be a critical initiating event in the carcinogenesis process. Total level of covalent binding in animal tissues is quantitatively related to carcinogenic potency and organ specificity of AFB1. Covalent binding to DNA is linearly related to AFB1 dose in animals over several orders of magnitude, and the effectiveness of protective agents is reflected in diminished DNA binding. AFB1 forms covalent adducts with DNA only at the N7 position of guanine following metabolic activatin through the 9, 10 oxide, and a qualitatively similar adduct profile is found in all cells (mammalian, microbial, and plant) in which epoxidation takes place. However, formation of the N7 guanine adduct in genomic DNA is non-random, with frequency of binding showing neighboring base effects. Adduct formation is substantially higher in actively transcribed gene sequences compared to untranscribed regions. The major AFB1-N7-guanine adduct in DNA is unstable, readily undergoing depurination or conversion to a stable formamido-pyrimdyl (FAPY) derivative. The kinetics of adduct formation and removal in rat liver have been thoroughly characterized following single and multiple exposures to AFB1. Adduct level rises rapidly to a maximum at two hours, then falls with a half-life of about 7.5 hours; within 24 hours after dosing only the FAPY-derivative remains. This derivative is stable over very long periods of time, and accumulates following multiple dosing. The potency with which AFB1 forms DNA adducts is also related to its mutagenicity for a very wide range of cell types, from prokaryotes of many types to mammalian, including human, cells. It also induces other genotoxic effects such as sister chromatid exchanges, recombination, chromosome aberrations as well as other clastogenic responses. In bacterial cells, the principal mutations generated by AFB1 have been characterized as G to T transversions or G to A transitions. These properties are relevant to the recent identification of activated Ki-ras oncogenes in rat liver tumors induced by AFB1. Investigation of the mechanisms of oncogene activation revealed that many of the tumors contain Ki-ras sequences with single base mutations in the 12th to 14th codons. The mutations characterized to date include mainly to G to T transversions, with G to A transitions observed less frequently. These findings are consistent with the conjecture that the oncogenes may have been mutated as a result of AFB1-DNA adduct formation and may have been involved in initiation of tumor development. Attempts are being made to determine the time and frequency at which these mutant alleles appear in preneoplastic liver.

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