IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
an α-class GST, mGSTA3-3, which has high affinity for aflatoxin B 1 8,9-epoxide
(Buetler & Eaton, 1992; Hayes et al., 1992). In contrast, rats do not constitutively express
a GST isoform with high epoxide-conjugating activity but do express an inducible αclass
GST (rGSTA5-5) with high activity. The induction of this enzyme plays a major
role in the resistance of rats to aflatoxin B 1-induced hepatocarcinogenicity following
treatment with enzyme inducers including oltipraz, ethoxyquin and butylated hydroxyanisole
(Kensler et al., 1986, 1987; Hayes et al., 1991, 1994).
A cross-species study of rats (Fischer 344, Sprague-Dawley and Wistar), mice
(C57BL), hamsters (Syrian golden) and guinea-pigs (Hartley) was conducted using doses
of aflatoxin B 1 between 1 and 80 μg/kg bw per day for up to 14 days by gavage (Wild
et al., 1996). Aflatoxin–albumin adducts were measured at 1, 3, 7 and 14 days and
hepatic aflatoxin B 1–DNA adducts were measured at the final time point. Both albumin
and DNA adducts were formed in the order rat > guinea-pig > hamster > mouse, with
similar ratios between the two biomarkers across species, suggesting that the albumin
adducts reflected hepatic DNA damage. Calculations from human environmental exposure
data and albumin adducts suggested that humans and rats — a sensitive species —
have similar formation of albumin adducts for a given exposure to aflatoxin.
In rats, the μ-class enzymes rGSTM2-2 and rGSTM2-3 can conjugate both the exoand
endo-epoxide of aflatoxin but the latter is the preferred substrate (Raney et al., 1992;
Johnson et al., 1997a). Wang et al. (2000) showed that the GST-conjugating ability of the
non-human primate, Macaca fascicularis (mf), towards the 8,9-epoxide was partially due
to a μ-class GST, mfaGSTM2-2, with 96% amino acid homology to the human hGSTM2.
The enzyme mfaGSTM2-2 was predominantly active towards the endo-epoxide, whereas
another enzyme, GSHA-GST, for which the encoding cDNA was not cloned, had activity
towards the exo-epoxide of aflatoxin. However, the activity was about two orders of
magnitude lower than that of the rodent α-class GSTs, mGSTA3-3 and rGSTA5-5.
In direct comparison, human and marmoset (Callithrix jacchus) hepatic microsomes
had similar rates of oxidation of aflatoxin B 1 to the 8,9-epoxide to those of macaques
(Macaca nemestrina), but GST activity towards the epoxide was below the detection
limit in the former two species (Bammler et al., 2000).
Stresser et al. (1994a) examined the influence of dietary indole-3-carbinol (found in
cruciferous vegetables) on the relative levels of different CYP isozymes known to metabolize
aflatoxin B 1 in male Fischer 344 rats. Diets containing 0.2% (w/w) indole-3-carbinol
given for seven days were shown to increase the microsomal concentrations of
CYP1A1, 1A2 and 3A1/2 (24-, 3.1- and 3.8-fold, respectively, compared with rats receiving
a control diet), with a smaller effect on 2B1/2 (1.7-fold) and no effect on CYP2C11.
The influence of dietary indole-3-carbinol on the aflatoxin B 1 glutathione detoxication
pathway and aflatoxin B 1–DNA adduct formation was also investigated. After seven days
of feeding a diet containing indole-3-carbinol (0.2% w/v), rats were administered
[ 3 H]aflatoxin B 1 (0.5 mg/kg bw) by intraperitoneal injection and killed after 2 h. The diet
with indole-3-carbinol inhibited the formation of aflatoxin B 1–DNA adducts in the liver
by 68%, based on analysis of DNA-bound radioactivity (Stresser et al., 1994b).