IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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observed in rat liver slices, albeit with significant interindividual variation. GSHconjugate
formation was not detected in the human liver samples.
It is probable that the apparent discrepancies between studies showing the elimination
of mercapturic acids in the urine of aflatoxin-exposed individuals (Wang et al.,
1999a) and the apparent lack of formation of glutathione conjugates in cytosolic
incubations with aflatoxin B 1 8,9-epoxide (Heinonen et al., 1996) are due to differences
in sensitivity of the analytical methods employed.
Rodent studies (see below) have demonstrated that viral damage to the liver affects
the metabolism of aflatoxin. Kirby et al. (1996a) examined the expression of CYP
enzymes in sections of normal human liver and in livers with hepatitis and cirrhosis. By
use of immunohistochemical techniques, it was shown that in sections infected with
hepatitis B virus (HBV) or hepatitis C virus (HCV), the concentration of CYP2A6 was
increased in hepatocytes immediately adjacent to areas of fibrosis and inflammation. In
the same tissues, CYP3A4 and CYP2B1 were somewhat increased and CYP1A2 was unaffected
compared with normal liver. In HCV-infected liver, CYP2A6, CYP3A4 and
CYP2B1 were increased in hepatocytes that had accumulated haemosiderin pigment.
4.1.2 Experimental systems
(a) Human tissues
IARC MONOGRAPHS VOLUME 82
Data published before 1993 were reviewed in IARC Monographs Volume 56 (IARC,
1993). The metabolism and major metabolites of aflatoxin B 1 are shown in Figures 3
and 4.
Gallagher et al. (1996) studied the kinetics of aflatoxin oxidation in human liver
microsomes and in lymphoblastoid microsomes expressing human CYP3A4 and
CYP1A2 cDNA: the K m was 41 μM for CYP1A2 and 140–180 μM (average affinity for
two binding sites) for CYP3A4. In the case of CYP3A4, the rate of product formation
dropped as the substrate concentration was reduced. In contrast, CYP1A2 has a higher
affinity for aflatoxin. In humans, at plausible serum aflatoxin concentrations, the rate of
formation of aflatoxin 8,9-epoxide will be determined by both the lower K m of CYP1A2
and the greater abundance of CYP3A4 in human liver.
The ability of the human lung to metabolize aflatoxin has been studied in the context
of the risk of pulmonary carcinogenesis from handling crops contaminated by aflatoxins.
Bioactivation of tritiated aflatoxin B 1 was demonstrated in fresh lung preparations from
patients undergoing lobectomy for lung cancer. Lipoxygenase and prostaglandin H
synthase activity was shown to be primarily responsible for aflatoxin activation, rather
than the CYP enzymes, which display a low level of activity in this tissue (Donnelly
et al., 1996).
Neal et al. (1998) compared the metabolism of aflatoxins B 1 and M 1 in vitro using
human liver microsomes. Indirect evidence was obtained for metabolism of aflatoxin M 1
to the 8,9-epoxide by trapping the reactive metabolite with Tris and GSH in the presence
of mouse cytosolic fraction. Human liver cytosol did not appear to mediate GSH