Abstract
Consumption of foods contaminated with aflatoxin B1
(AFB1) is a recognized risk factor for developing
hepatocellular carcinomas (HCCs). The mutational signature of
AFB1 is characterized by high frequency G >
T transversions in a limited subset of trinucleotide sequences. The
8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin
B1 (AFB1-FapyGua) has been implicated as
the primary DNA lesion responsible for AFB1-induced
mutations. This study evaluated the mutagenic potential of
AFB1-FapyGua in four contexts, including hot- and
cold-spot sequences as apparent in the mutational signature. Vectors
containing AFB1-FapyGua were replicated in primate cells
and the products of replication were isolated and sequenced. Regardless
of the sequence context, AFB1-FapyGua caused base
substitutions at frequencies of ~ 80-90%, with G
> T transversions being most common. Spectra of mutations
were only slightly modulated by the sequence context. These data suggest
that mechanism(s) defining sequence context-dependent distribution of
AFB1-induced mutations likely operates prior to
replication.