IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

AFLATOXINS 217
reduction of the dialdehydic phenolate ion to a dialcohol; this enzyme has been
characterized in both rats and humans (Hayes et al., 1993; Ireland et al., 1998; Knight
et al., 1999).
The role of epoxide hydrolase in hydrolysis of aflatoxin B 1 8,9-epoxide has been
investigated (Guengerich et al., 1996; Johnson et al., 1997a,b) with respect to the
observed association between epoxide hydrolase genotype and risk for hepatocellular
carcinoma in aflatoxin-exposed populations (McGlynn et al., 1995; Tiemersma et al.,
2001). If the enzyme is involved, its contribution may be limited, given the rapid nonenzymatic
hydrolysis mentioned above (Guengerich et al., 1998).
Oltipraz, an antischistosomal drug, acts as a potent inhibitor of aflatoxin-induced
hepatocarcinogenesis in animal models. A total of 234 healthy adults from Qidong
(China) were assigned to receive 125 mg oltipraz daily, 500 mg oltipraz weekly or a
placebo. Urinary aflatoxin metabolites were quantified by sequential immunoaffinity
chromatography and liquid chromatography coupled to mass spectrometry or fluorescence
detection. One month of weekly administration of 500 mg oltipraz led to a 51%
decrease in the amount of aflatoxin M 1 excreted in urine compared with administration
of a placebo (p = 0.030), but it had no effect on concentrations of aflatoxin–mercapturic
acid (p = 0.871). Daily intervention with 125 mg oltipraz led to a 2.6-fold increase in
median aflatoxin–mercapturic acid excretion (p = 0.017) but had no effect on excreted
aflatoxin M 1 levels (p = 0.682). It was concluded that the higher dose of oltipraz
inhibited aflatoxin activation, whereas the lower dose increased GSH conjugation of
aflatoxin 8,9-epoxide (Wang et al., 1999a). Among other things, this clinical trial
demonstrates that the results of studies conducted in vitro on the major pathways of aflatoxin
processing (discussed below) are consistent with human data.
Kirby et al. (1993) examined liver tissues from 20 liver cancer patients from
Thailand, an area where exposure to aflatoxin occurs. The activity of hepatic CYP isoenzymes
and GST was examined and compared with the in-vitro metabolism of aflatoxin
B 1. There was considerable inter-individual variation in activity of CYP enzymes,
including CYP3A4 (57-fold), CYP2B6 (56-fold) and CYP2A6 (120-fold). In microsomal
preparations from liver tumours, metabolism of aflatoxin B 1 to the 8,9-epoxide
and aflatoxin Q 1 (the major metabolites) was related to the concentration of CYP3A3/4
and CYP2B6. There was significantly reduced activity of major CYP proteins in microsome
preparations from liver tumours compared with those from adjacent non-tumour
areas in the liver. The major classes of cytosolic GSTs (α, μ and π) were also analysed
in normal and tumorous liver tissue. The activity of α and μ class proteins was decreased
and π increased in the majority of tumour cytosols compared with normal liver. Cytosolic
GST activity was significantly lower in liver tumours than in normal liver. There
was no detectable conjugation of aflatoxin B 1 8,9-epoxide to GSH by microsomal
preparations from either normal liver or liver tumour tissue.
Heinonen et al. (1996) studied aflatoxin B 1 metabolism in human liver slices from
three donors by incubating the tissue with 0.5 μM [ 3 H]aflatoxin B 1 for 2 h. The rates of
oxidative metabolism of aflatoxin B 1 to aflatoxins Q 1, P 1 and M 1 were similar to those