Page 230 - The Toxicology of Fishes

210 The Toxicology of Fishes

O O O O
OH OH
O O
GS OH
O O
Epoxide
O OCH 3 GST? hydrolase ? O OCH 3

O O
O O Protein Schiff–Base
adduct formation
DNA adducts
O
O OCH 3
AFB 1–8,9–epoxide
Protein adducts

CYP450
O OH
O O
O
O
O
O
O OCH 3
O
OCH 3
AFB Aflatoxicol
CYP450 1

O O O O O O

O O O
OH
O O OH O
O O O OH
OCH 3 OCH 3
AFM 1 AFQ 1 AFP 1

Glucuronide and sulfate
conjugates
FIGURE 4.23 Biochemical pathways for aflatoxin (AFB 1 ) biotransformation.

only 4 weeks resulted in a tumor incidence of 62%. Remarkably, static renewal exposure of fertilized
rainbow trout eggs (embryos) to 500 ppb (in the bathing medium) AFB for 15 minutes resulted in 62%
1
incidence of hepatic tumors 12 months after hatching (Hendricks, 1994).
Studies in several species have demonstrated that AFB requires microsomal oxidation to the reactive
1
AFB -exo-8,9-epoxide (AFBO) (Figure 4.23) to exert its hepatocarcinogenic effects. In addition to
1
producing AFBO, chemical and enzymatic epoxidations of AFB can also result in the formation of an
1
endo-AFB epoxide stereoisomer (Raney et al., 1992a). Although the endo-epoxide is less susceptible
1
to hydrolysis compared to the exo-conformation, the exo-epoxide is much more efficient at forming
DNA adducts and is much more mutagenic than the endo-epoxide (Raney et al., 1992b, 1993). AFB 1
carcinogenic potency is highly correlated with the extent of total AFBO–DNA adducts formed in vivo