Page 563 - The Toxicology of Fishes

Chemical Carcinogenesis in Fishes 543

O O O O
O
O O O
H H
O
O O
CH Cl 2
2
H O OCH 3 H O OCH 3
1 rt 15 min AFB1-E (6)

OCH 3
O
O O O
O O H H
O O O
H O OH
DNA
O N+
HN
H O OCH 3
H N N N
5 2
O
O PO OPO 3
3
AFB1–N -Gua
7
DNA Adduct (6)

FIGURE 12.3 Metabolic activation of AFB 1 and DNA adduct formation.

same guanine adduct as the epoxide metabolite in trout (Bailey et al., 1994). In trout, AFB –DNA adducts
1
are associated with G→T transversions in codons 12 and 13 of Ki-ras (Bailey et al., 1988); however,
in rats, although the same G in codon 12 of ras is targeted in AFB -induced liver tumors, the prominent
1
mutation observed is a G→A transition, with minor G→T transversions in the same codon. Although
AFB targets the same nucleotide in trout and rat ras, it is puzzling that presumably the same type of
1
AFB –deoxyguanine adduct in ras codon 12 results in different types of prominent mutations between
1
trout and rats. A thorough comparison of reactivity of mammalian and trout DNA replication polymerases
may reveal differences in the way the polymerases interact with AFB –DNA adducts.
1
DMBA
In mammalian embryo cells, three prominent DNA adducts are derived from DMBA diol-epoxide: anti
dihydrodiol epoxide-deoxyguanosine, anti dihydrodiol epoxide-deoxyadenosine, and syn dihydrodiol
epoxide-deoxyadenosine (Pigott and Dipple, 1988). Various mutations attributed to these adducts have
been described. In the mammary gland of Big Blue rats, DMBA induced mutations in lacI, and A→T
(44%) and G→T (25%) transversions were the predominant types (Manjanatha et al., 2000). In addition,
DMBA can be activated by one-electron oxidation, as demonstrated by the depurinating DNA adducts
observed in mouse skin (Devanesan et al., 1993). DMBA is known to bind covalently to DNA in trout,
and there is evidence that the overall level of adduct formation is comparable to that in mammals (Schnitz
and O’Connor, 1992). In trout, however, a much different spectrum of adducts in liver Ki-ras was
demonstrated (Fong et al., 1993), with G→T transversions and G→A transitions dominating in codon
12. Because in mammalian systems the syn dihydrodiol epoxide of DMBA nearly exclusively forms
adenine adducts, it was predicted (Fong et al., 1993) that the abundance of guanine-based mutations in
trout Ki-ras may reflect different metabolic paths for DMBA bioactivation. Additional studies indicate
that different types of DMBA–DNA adducts are formed in trout cells compared to those adducts formed
in mammalian cells. Such differences in DNA adducts may contribute to the differences in types of