Biochemical and Histopathological Effects of Aflatoxin on ...

._ the former salmonid is clearly more sensitive to the hepatocarcinogenic
effects <strong>of</strong> AFB1 (Bailey et al, 1988). Activated AFB I binds exclusively with
guanyl residues in DNA, <strong>and</strong> the AFB 1-N7-Gua adduct are by far the most
predominant form. Although AFB 1 binds exclusively with guanyl residues,
not all guanines in r<strong>and</strong>om sequences <strong>of</strong> double str<strong>and</strong>ed DNA appear to be
equally reactive, <strong>and</strong> the frequency <strong>of</strong> attack among guanyl sites can vary by
ten fold or more (D Andrea <strong>and</strong> Haseltine, 1978; Misra et al, 1983; Muench
et al, 1983). Not all damains in chromatin are equally accessible to AFB 1 .
Intemucleosomal, or linker DNA is roughly five times as likely to become
adducted with AFB I as is nucleosomal core DNA in rainbow trout liver,
following intraperitoneal injection (Bailey et al, 1980).
More recent evidence indicates that the total level <strong>of</strong> DNA adduct
formation by AFB1- (as well as by other chemical carcinogens) may not
provide an accurate indicator <strong>of</strong> the alkylation potential as genetic "hot­
spots", such as a proto-oncogene. Activation <strong>of</strong> proto-oncogenes in animal
<strong>and</strong> human tumours <strong>and</strong> in cell transformation systems has been shown to
involve specific mutations in base sequence, an event postulated to play a
cmtial role in the early stages <strong>of</strong> chemical carcinogenesis. Chang et al (1991)
was the first to demonstrate ras gene activation by a known carcinogen in
any fish species. Using PCR <strong>and</strong> oligonucleotide hybridization methods, a
high proportion <strong>of</strong> the aflatoxin BI - initiated tumour DNAs showed evidence
<strong>of</strong> activating point mutations in the trout ras-1 gene. Among these a
predominant lesion was a GGA to GTA transversion in codon 12. This
mutation is the most commonly found molecular lesion in rodent
carcinogenesis models <strong>and</strong> many human tumours. Of the remaining mutant
ras genotypes, two were codon 13 GGT to GTT transversions, <strong>and</strong> one was a
codon 12 GGA to AGA transition.
16