IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

GSTs, namely hGSTA1-1 and hGSTA2-2, also lack significant activity (Raney et al.,
1992; Buetler et al., 1996; Johnson et al., 1997a,b). Some conjugating activity was
expressed by human μ-class GSTs M1a-1a and M2-2, although mostly towards the endoepoxide
(Raney et al., 1992).
Langouët et al. (1995) investigated metabolism of aflatoxin B 1 in primary human
hepatocytes from eight human liver donors with or without pretreatment by oltipraz.
Parenchymal cells obtained from the three GSTM1-positive livers metabolized aflatoxin
B 1 to aflatoxin M 1 and to aflatoxin B 1–glutathione conjugates, but no such conjugates
were formed in the cells lacking GSTM1. Although oltipraz treatment of the cells
induced GSTs A2, A1 and M1, it resulted in decreased formation of aflatoxin M 1 and
aflatoxin B 1 oxides due to inhibition of CYP1A2 and CYP3A4.
(b) Experiments on animals and animal tissues
AFLATOXINS 221
Kirby et al. (1996b) demonstrated that viral infections causing liver injury alter the
activity of aflatoxin-metabolizing enzymes in human liver. This has also been shown in
transgenic mice that overproduce the HBV large envelope protein, which results in
progressive liver cell injury, inflammation and regenerative hyperplasia. The activity of
CYP2A5 and CYP3A and a GSTα isoenzyme was examined in these mice. Increased
activity and altered distribution of CYP2A5 were shown to be associated with the development
of liver injury. The amount of CYP3A was also increased, while GSTα enzyme
concentrations were the same in transgenic mice and in otherwise isogenic, non-transgenic
mice (Kirby et al., 1994a).
Fetal rat liver contains a GST that forms a conjugate with aflatoxin B 1 8,9-epoxide,
identified as a GSTα. By means of immunoblotting and enzyme assays it was shown that
liver from adult female rats contains concentrations of one of the enzyme subunits (Yc 2)
about 10-fold higher than those in liver from adult male rats. This may contribute to the
relative insensitivity of female rats to aflatoxin B 1 (Hayes et al., 1994).
In addition to CYP-mediated activation, aflatoxin B 1 8,9-epoxide can also be formed
through metabolism by lipoxygenase and prostaglandin H synthase isolated from guineapig
tissues and ram seminal vesicles, respectively (Battista & Marnett, 1985; Liu &
Massey, 1992). In some organs, for example guinea-pig kidney, the contributions of CYP
and prostaglandin H synthase to formation of the epoxide are similar (Liu et al., 1990).
There are marked species differences in sensitivity to aflatoxin carcinogenesis
(Gorelick, 1990; Eaton & Gallagher, 1994; Eaton & Groopman, 1994). For example, the
adult mouse is almost completely refractory to tumour formation except under conditions
of partial hepatectomy or liver injury through expression of HBV antigens. In
contrast, the rat is extremely sensitive (see Section 3). A considerable part of this interspecies
variation is now understood in terms of differences in activity of aflatoxin-metabolizing
enzymes in the pathways described above. Microsomal preparations from mice
actually exhibit higher specific activity for aflatoxin B 1 8,9-epoxide production than the
rat (Ramsdell & Eaton, 1990). However, in the mouse, the resistance to aflatoxin carcinogenesis
is largely if not exclusively explained by the constitutive hepatic expression of